hh - AI Gene Review

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001708 cell fate specification	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Hedgehog ligands assign identity to cells in a concentration-dependent way, and this IBA row propagates that shared developmental output from PAINT node PTN001726121, whose seeds include Drosophila hh itself alongside vertebrate ligands. Reason: The node placement is sound - concentration-dependent assignment of cell identity is what Hedgehog ligands do in flies and vertebrates alike, and the fly gene is one of the descendant evidences used to place it. Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0001745 compound eye morphogenesis	IMP PMID:16651542 Roadkill attenuates Hedgehog responses through degradation o...	KEEP AS NON CORE	Summary: Hh drives progression of the morphogenetic furrow and continues to act behind it; the cited study of the Cullin3 adaptor Roadkill reports a role for Hh in organisation and survival of cells in the eye. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Compound eye morphogenesis is one of the best-documented tissue outcomes of fly Hh signalling, but it is an outcome of graded ligand activity rather than an activity of the ligand. Supporting Evidence: PMID:16651542 rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells.
GO:0001746 Bolwig's organ morphogenesis	IMP PMID:10704398 Transcriptional regulation of atonal required for Drosophila...	KEEP AS NON CORE	Summary: Formation of the larval light-sensing Bolwig's organ, and the atonal expression it depends on, require hh together with eyes absent and sine oculis. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:10704398 Here, we showed that Bolwig's organ formation and atonal expression are controlled by the concerted function of hedgehog, eyes absent and sine oculis.
GO:0001751 compound eye photoreceptor cell differentiation	TAS PMID:15273984 Coming to our senses.	KEEP AS NON CORE	Summary: Photoreceptor differentiation in the compound eye follows the Hh-driven morphogenetic furrow, so the term is correct for hh; the cited review, however, is a general essay on sensory organ development that discusses Decapentaplegic, Wingless, ecdysone and atonal rather than Hedgehog. Reason: The term itself is well supported for hh by the furrow-progression work cited elsewhere in this review (PMID:8252628), so it is kept rather than removed. Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The citation is a weak anchor for the claim and is flagged in the reference review.
GO:0002052 positive regulation of neuroblast proliferation	IMP PMID:12645928 Drosophila perlecan modulates FGF and hedgehog signals to ac...	KEEP AS NON CORE	Summary: Hh activates neuroblast (neural stem cell) division in the larval brain, in a manner dependent on the Perlecan homolog Trol. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. Proliferation of the responding neuroblasts is driven by their own machinery once the pathway is activated. Supporting Evidence: PMID:12645928 Like FGF, Hh activates stem cell division in the larval brain in a Trol-dependent fashion.
GO:0002385 mucosal immune response	IMP PMID:25639794 Bacterial uracil modulates Drosophila DUOX-dependent gut imm...	KEEP AS NON CORE	Summary: Hh signalling is required in the adult gut for the uracil-induced, Cad99C- and DUOX-dependent production of reactive oxygen species that constitutes the epithelial immune response to bacterial infection. Reason: A genuine adult, non-developmental role of the ligand, well documented by RNAi knockdown and recorded in the UniProt entry: hh loss abolishes Cad99C-dependent endosome formation and DUOX-dependent ROS production in the gut. It is nonetheless a tissue-level physiological outcome of the same ligand activity rather than an activity of the protein, so it is kept as non-core. Supporting Evidence: PMID:25639794 Here, we show that the Hedgehog (Hh) signaling pathway modulates uracil-induced DUOX activation.
GO:0004175 endopeptidase activity	ISS GO_REF:0000024	MODIFY	Summary: The C-terminal Hint/Hog domain does cleave the precursor, but the leaving group is cholesterol rather than water: cleavage and cholesterol esterification are one reaction cycle, which GO:0140853 describes exactly and which is already annotated to hh from the same ISS source. Reason: Endopeptidase activity is defined as hydrolysis of internal peptide bonds, and Hedgehog self-processing is a transesterification in which the thioester intermediate is resolved by the 3-beta-hydroxyl of cholesterol, not by water. The mechanism was established on the Drosophila protein itself, whose crystal structure identified the active-site residues and whose D303A mutation abolishes cholesterol transfer. The same MODIFY call was made on the human orthologue review (genes/human/SHH). Note that the Hedgehog module (modules/hedgehog_signaling.yaml) currently types the hh_autoprocessing annoton with GO:0004175; that divergence is deliberate and flagged rather than silently accepted. Proposed replacements: cholesterol-protein transferase activity Supporting Evidence: PMID:9335337 The approximately 25 kDa carboxy-terminal domain of Drosophila Hedgehog protein (Hh-C) possesses an autoprocessing activity that results in an intramolecular cleavage of full-length Hedgehog protein and covalent attachment of a cholesterol moiety to the newly generated amino-terminal fragment.
GO:0005113 patched binding	IBA GO_REF:0000033	ACCEPT	Summary: Patched binding is asserted at PAINT node PTN001726121, seeded by Drosophila hh together with mouse genes and all three human paralogs; it is the interaction that defines membership of the Hedgehog ligand family. Reason: Retained as a core molecular function. Binding Patched is the step that defines a Hedgehog ligand: the dually lipidated Hh-Np released from posterior-compartment cells engages a receptor complex of Patched with Ihog or Boi on anterior cells, and that binding event is what relieves Patched-mediated inhibition of Smoothened. This is an activity of the gene product itself rather than a downstream consequence of it. The fly gene appearing among the node's own seeds is expected: its experimental annotation is one of the descendant evidences the PAINT curator used to place the assertion, and the IBA then adds that the function is inherited rather than lineage-specific. The family review (interpro/panther/PTHR11889) assesses this node as SOUND.
GO:0005113 patched binding	IPI PMID:20048000 Genetic and biochemical definition of the Hedgehog receptor.	ACCEPT	Summary: Genetic and biochemical dissection of the Drosophila receptor shows that Ptc and Ihog together bind Hh with high affinity and that both are required for the biological response. Reason: Retained as a core molecular function. Binding Patched is the step that defines a Hedgehog ligand: the dually lipidated Hh-Np released from posterior-compartment cells engages a receptor complex of Patched with Ihog or Boi on anterior cells, and that binding event is what relieves Patched-mediated inhibition of Smoothened. This is an activity of the gene product itself rather than a downstream consequence of it. This row is the direct interaction evidence in the fly, and it also records the point at which fly and vertebrate biology differ: vertebrate SHH binds PTCH1 on its own, whereas high-affinity Hh binding in Drosophila requires Ihog or Boi alongside Ptc. Supporting Evidence: PMID:20048000 We demonstrate that Ihog interacts directly with Ptc, is required for presentation of Ptc on the cell surface, and that Ihog and Ptc are both required for high-affinity Hh binding. PMID:20048000 On the basis of their joint roles in ligand binding, signal transduction, and receptor trafficking, we conclude that Ihog and Ptc together constitute the Drosophila Hh receptor.
GO:0005113 patched binding	NAS PMID:1340474 The Drosophila hedgehog gene is expressed specifically in po...	ACCEPT	Summary: An author statement in the original hh cDNA paper that Hh acts through patched; the claim is correct and is independently established by the IPI and IBA rows for the same term. Reason: Retained as a core molecular function. Binding Patched is the step that defines a Hedgehog ligand: the dually lipidated Hh-Np released from posterior-compartment cells engages a receptor complex of Patched with Ihog or Boi on anterior cells, and that binding event is what relieves Patched-mediated inhibition of Smoothened. This is an activity of the gene product itself rather than a downstream consequence of it. The evidence code is weak on its own - a non-traceable author statement from a 1992 expression study - but the assertion it makes is the one supported by direct interaction evidence elsewhere in this set, so there is nothing to correct.
GO:0005509 calcium ion binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Calcium binding is propagated from PAINT node PTN001726121. UniProt records two Ca(2+) sites on Drosophila Hh by similarity to human SHH, at residues 149, 150, 155, 185, 186, 189 and 191, and the fly sequence carries Glu, Glu, Asp, Thr, Glu, Asp and Asp at those positions - the acidic and hydroxyl set expected of a coordinating shell. Reason: The family review (interpro/panther/PTHR11889) leaves this node's depth UNRESOLVED because its three seeds are human paralogs while the node sits at Eumetazoa, and asks for the sequence question to be settled. The check above supports conservation in Drosophila rather than contradicting it, so the row is kept. It is non-core because the metal is a structural feature of the signalling domain that stabilises the surface used for receptor contact, not an activity of the protein; the same call was made on the human orthologue review.
GO:0005515 protein binding	IPI PMID:15691765 The Drosophila ortholog of the human Wnt inhibitor factor Sh...	REMOVE	Summary: An interaction with Shifted (Shf), the Drosophila WIF-family protein required for Hh stability and spreading. The interaction is real, but bare protein binding carries no functional information and no more specific molecular function term is supported by the cited work. Reason: Generic protein binding is uninformative as a molecular function, and removal does not mean the reported interaction is false. Shf is a secreted modulator of Hh diffusion rather than a receptor or a catalytic partner, so no evidence-backed replacement term is available; the biology is captured by the morphogen activity and extracellular region annotations instead. Supporting Evidence: PMID:15691765 In contrast, Shf is required for Hh stability and for lipid-modified Hh diffusion.
GO:0005515 protein binding	IPI PMID:16630821 The ihog cell-surface proteins bind Hedgehog and mediate pat...	MODIFY	Summary: An interaction with Ihog (Interference hedgehog), the fibronectin-domain co-receptor that, together with Patched, constitutes the Drosophila Hedgehog receptor. Bare protein binding records the interaction without saying what it is. Reason: Generic protein binding carries no functional information, but here the partner is recorded and the literature supports something specific: Ihog binds Hh directly through its first fibronectin type III repeat, is absolutely required for the Hh response, and forms the receptor together with Ptc. GO:0005113 patched binding is not the right replacement because the recorded partner is Ihog and not Ptc; GO:0005102 signaling receptor binding states what the interaction is - engagement of a component of the receptor that transduces the signal - without overstating it. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:16630821 The first of two extracellular fibronectin type III (FNIII) domains of the Ihog protein mediates a specific interaction with Hh protein in vitro
GO:0005515 protein binding	IPI PMID:17077139 Structure of a heparin-dependent complex of Hedgehog and Iho...	MODIFY	Summary: An interaction with Ihog (Interference hedgehog), the fibronectin-domain co-receptor that, together with Patched, constitutes the Drosophila Hedgehog receptor. Bare protein binding records the interaction without saying what it is. This row is anchored to the crystal structure of the Hh-Ihog complex. Reason: Generic protein binding carries no functional information, but here the partner is recorded and the literature supports something specific: Ihog binds Hh directly through its first fibronectin type III repeat, is absolutely required for the Hh response, and forms the receptor together with Ptc. GO:0005113 patched binding is not the right replacement because the recorded partner is Ihog and not Ptc; GO:0005102 signaling receptor binding states what the interaction is - engagement of a component of the receptor that transduces the signal - without overstating it. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:17077139 These results establish that Hh directly binds Ihog and provide the first demonstration of a specific role for heparin in Hh responsiveness.
GO:0005515 protein binding	IPI PMID:20048000 Genetic and biochemical definition of the Hedgehog receptor.	MODIFY	Summary: An interaction with Ihog (Interference hedgehog), the fibronectin-domain co-receptor that, together with Patched, constitutes the Drosophila Hedgehog receptor. Bare protein binding records the interaction without saying what it is. This row is anchored to the paper that defines Ihog plus Ptc as the Drosophila Hh receptor. Reason: Generic protein binding carries no functional information, but here the partner is recorded and the literature supports something specific: Ihog binds Hh directly through its first fibronectin type III repeat, is absolutely required for the Hh response, and forms the receptor together with Ptc. GO:0005113 patched binding is not the right replacement because the recorded partner is Ihog and not Ptc; GO:0005102 signaling receptor binding states what the interaction is - engagement of a component of the receptor that transduces the signal - without overstating it. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:20048000 On the basis of their joint roles in ligand binding, signal transduction, and receptor trafficking, we conclude that Ihog and Ptc together constitute the Drosophila Hh receptor.
GO:0005515 protein binding	IPI PMID:31209108 The Drosophila Hedgehog receptor component Interference hedg...	MODIFY	Summary: An interaction with Ihog (Interference hedgehog), the fibronectin-domain co-receptor that, together with Patched, constitutes the Drosophila Hedgehog receptor. Bare protein binding records the interaction without saying what it is. This row is anchored to the study showing that Hh competes with the trans-homophilic Ihog-Ihog interaction, which maps to the same surface of the first fibronectin repeat that Hh engages. Reason: Generic protein binding carries no functional information, but here the partner is recorded and the literature supports something specific: Ihog binds Hh directly through its first fibronectin type III repeat, is absolutely required for the Hh response, and forms the receptor together with Ptc. GO:0005113 patched binding is not the right replacement because the recorded partner is Ihog and not Ptc; GO:0005102 signaling receptor binding states what the interaction is - engagement of a component of the receptor that transduces the signal - without overstating it. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:31209108 We further demonstrate that Hh interferes with Ihog-mediated homophilic interactions by competing for Ihog binding.
GO:0005576 extracellular region	IBA GO_REF:0000033	ACCEPT	Summary: The processed ligand is released from the producing cell and is active in the extracellular region; this IBA row propagates that from PAINT node PTN001726121, whose seeds include Drosophila hh. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. The is_active_in relation is the right one here, and the family review assesses this node as SOUND.
GO:0005576 extracellular region	IDA PMID:11486055 Skinny hedgehog, an acyltransferase required for palmitoylat...	ACCEPT	Summary: Biochemical characterisation of Hh from wild-type and rasp mutant cells, which established that the secreted N-product carries N-terminal palmitate in addition to C-terminal cholesterol. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through.
GO:0005576 extracellular region	IDA PMID:12372301 Hedgehog-mediated patterning of the mammalian embryo require...	ACCEPT	Summary: Analysis of Dispatched function, in which Drosophila disp rescue and a direct biochemical assay of Disp-dependent release of soluble Hh proteins were used together. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. The paper's title foregrounds the mouse homolog, but it reports Drosophila disp rescue experiments as well, and the curator will have read the full text. Supporting Evidence: PMID:12372301 We have developed a biochemical assay that directly measures the activity of Disp proteins in release of soluble Hh proteins.
GO:0005576 extracellular region	IDA PMID:17484784 Quantitative analysis of Hedgehog gradient formation using a...	ACCEPT	Summary: Quantitative imaging of inducibly expressed GFP-tagged Hh in the wing disc, which localised Hh particles to the extracellular space when cholesterol modification and endocytosis were both blocked. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. Supporting Evidence: PMID:17484784 In the absence of both cholesterol and endocytosis, Hh particles accumulated in the extracellular space.
GO:0005576 extracellular region	IDA PMID:18219274 Reggie-1/flotillin-2 promotes secretion of the long-range si...	ACCEPT	Summary: Analysis of Reggie-1/flotillin-2, which changes the amount of Hh secreted and the distance it spreads. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. Supporting Evidence: PMID:18219274 Reggie-1 loss-of-function results in reduced spreading of the morphogens, while its overexpression stimulates secretion of Wnt and Hedgehog and expands their diffusion.
GO:0005576 extracellular region	IDA PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d...	ACCEPT	Summary: Cultured-cell assays in which S2 cells were stimulated with medium conditioned by HhN-expressing cells, showing that the ligand is present and active outside the producing cell. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. Supporting Evidence: PMID:22537496 S2 cells were co-transfected with Myc-SmoWT and tub-Ci followed by treatment with HhN-conditioned medium.
GO:0005576 extracellular region	IDA PMID:8287482 Hedgehog is a signaling protein with a key role in patternin...	ACCEPT	Summary: Antibody detection of Hh protein crossing parasegment and compartment borders into cells that express neither engrailed nor hedgehog. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. Supporting Evidence: PMID:8287482 We show here that the hedgehog protein is secreted, and it can cross embryo parasegment borders and the anterior-posterior compartment border of imaginal discs to neighboring cells that express neither engrailed nor hedgehog.
GO:0005576 extracellular region	IMP PMID:7552175 Secretion of the amino-terminal fragment of the hedgehog pro...	ACCEPT	Summary: Mutational dissection of the hh coding region showing that secretion of the amino-terminal fragment is necessary for signalling. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through.
GO:0005576 extracellular region	TAS Reactome:R-DME-209178	ACCEPT	Summary: A Reactome event placing the processed N-HH product in the extracellular region, where it binds the Patched receptor complex, is handed over by Dispatched, and associates with heparan sulfate proteoglycans. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. The Reactome compartment assignment is correct for these events even where the same model mislocalises the upstream steps.
GO:0005576 extracellular region	TAS Reactome:R-DME-209271	ACCEPT	Summary: A Reactome event placing the processed N-HH product in the extracellular region, where it binds the Patched receptor complex, is handed over by Dispatched, and associates with heparan sulfate proteoglycans. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. The Reactome compartment assignment is correct for these events even where the same model mislocalises the upstream steps.
GO:0005576 extracellular region	TAS Reactome:R-DME-209272	ACCEPT	Summary: A Reactome event placing the processed N-HH product in the extracellular region, where it binds the Patched receptor complex, is handed over by Dispatched, and associates with heparan sulfate proteoglycans. Reason: Retained as a core location. Hh-Np is released from the producing cell and acts on cells across the compartment boundary, so the extracellular region is where the ligand's receptor-binding activity is executed, not merely a compartment it passes through. The Reactome compartment assignment is correct for these events even where the same model mislocalises the upstream steps.
GO:0005634 nucleus	EXP PMID:1280560 Molecular organization and embryonic expression of the hedge...	REMOVE	Summary: Nuclear localisation attributed to Hh on the basis of a 1992 study that reported nuclear localisation of the hh RNA, not of the Hh protein. Reason: The cited paper is a molecular-organisation and expression study, and the localisation it reports is of the hh transcript, not of the protein: "This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic." No anti-Hh antibody data appear in it. The protein carries a cleaved N-terminal signal sequence, is co-translationally translocated into the secretory pathway, autoprocesses in the ER lumen and is released from the cell; there is no evidence for a nucleoplasmic or cytosolic pool, and no mechanism by which a signal-peptide-bearing ligand would reach either. This is not a case of second-guessing an assay that is hidden from us - the abstract states what was observed - so the annotation is removed rather than downgraded. Supporting Evidence: PMID:1280560 This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic.
GO:0005634 nucleus	IEA GO_REF:0000044	REMOVE	Summary: The UniProt subcellular-location keyword mapping propagates the same nucleus assignment, which traces back to the RNA localisation reported in PMID:1280560. Reason: The cited paper is a molecular-organisation and expression study, and the localisation it reports is of the hh transcript, not of the protein: "This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic." No anti-Hh antibody data appear in it. The protein carries a cleaved N-terminal signal sequence, is co-translationally translocated into the secretory pathway, autoprocesses in the ER lumen and is released from the cell; there is no evidence for a nucleoplasmic or cytosolic pool, and no mechanism by which a signal-peptide-bearing ligand would reach either. This is not a case of second-guessing an assay that is hidden from us - the abstract states what was observed - so the annotation is removed rather than downgraded. The IEA row inherits the error from the UniProt SUBCELLULAR LOCATION statement and should be corrected at that source as well.
GO:0005737 cytoplasm	EXP PMID:1280560 Molecular organization and embryonic expression of the hedge...	TOO GENERAL	Summary: True but broad: entailed by cytoplasmic vesicle, endocytic vesicle and endosome, kept in this review. Reason: GO's cytoplasm covers everything inside the plasma membrane except the nucleus, organelles and secretory compartments included, so cytoplasmic vesicle, endocytic vesicle and endosome, kept in this review, entail this term and the claim is true. TOO_GENERAL rather than REMOVE. The objection is a reason not to annotate a narrower term such as cytosol, not to remove this one. Objection recorded at removal: The cited paper is a molecular-organisation and expression study, and the localisation it reports is of the hh transcript, not of the protein: "This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic." No anti-Hh antibody data appear in it. The protein carries a cleaved N-terminal signal sequence, is co-translationally translocated into the secretory pathway, autoprocesses in the ER lumen and is released from the cell; there is no evidence for a nucleoplasmic or cytosolic pool, and no mechanism by which a signal-peptide-bearing ligand would reach either. This is not a case of second-guessing an assay that is hidden from us - the abstract states what was observed - so the annotation is removed rather than downgraded. Even setting the RNA-versus-protein confusion aside, cytoplasm would be an uninformative location for a protein whose entire itinerary is the secretory pathway and the cell exterior. Summary at removal: Cytoplasmic localisation attributed to Hh from the same 1992 study, which reported that the hh RNA shifts from nuclear to cytoplasmic at stage 11. Supporting Evidence: PMID:1280560 This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic.
GO:0005737 cytoplasm	IEA GO_REF:0000044	TOO GENERAL	Summary: True but broad: entailed by cytoplasmic vesicle, endocytic vesicle and endosome, kept in this review. Reason: GO's cytoplasm covers everything inside the plasma membrane except the nucleus, organelles and secretory compartments included, so cytoplasmic vesicle, endocytic vesicle and endosome, kept in this review, entail this term and the claim is true. TOO_GENERAL rather than REMOVE. The objection is a reason not to annotate a narrower term such as cytosol, not to remove this one. Objection recorded at removal: The cited paper is a molecular-organisation and expression study, and the localisation it reports is of the hh transcript, not of the protein: "This RNA is localized predominantly within nuclei until stage 10, when the localization becomes primarily cytoplasmic." No anti-Hh antibody data appear in it. The protein carries a cleaved N-terminal signal sequence, is co-translationally translocated into the secretory pathway, autoprocesses in the ER lumen and is released from the cell; there is no evidence for a nucleoplasmic or cytosolic pool, and no mechanism by which a signal-peptide-bearing ligand would reach either. This is not a case of second-guessing an assay that is hidden from us - the abstract states what was observed - so the annotation is removed rather than downgraded. The IEA row inherits the error from the UniProt SUBCELLULAR LOCATION statement and should be corrected at that source as well. Summary at removal: The UniProt subcellular-location keyword mapping propagates the same cytoplasm assignment, which traces back to the RNA localisation reported in PMID:1280560.
GO:0005768 endosome	IDA PMID:17484784 Quantitative analysis of Hedgehog gradient formation using a...	KEEP AS NON CORE	Summary: Hh-GFP is detected in intracellular, Dynamin-dependent punctate structures in receiving cells, a pool distinct from the extracellular ligand. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Endosomal Hh in receiving cells is a real and functionally important pool - receptor-mediated endocytosis shapes the gradient - but it is a trafficking compartment. Supporting Evidence: PMID:17484784 Inhibition of Dynamin-dependent endocytosis blocked formation of intracellular Hh particles, but did not prevent movement of newly synthesized Hh to the apical or basolateral surfaces of target cells.
GO:0005829 cytosol	TAS Reactome:R-DME-209271	REMOVE	Summary: A cytosolic location taken from a Drosophila Reactome model that places Hh autocleavage, Rasp-mediated palmitoylation and Dispatched-dependent release in the cytosol. Reason: Hh is never exposed to the cytosol. The precursor carries a cleaved signal sequence and is translocated into the endoplasmic reticulum, where the Hint/Hog domain performs cleavage and cholesterol transfer; Rasp palmitoylates the new N terminus within the secretory pathway; and Dispatched then releases the lipidated product from the plasma membrane to the outside. The cached Drosophila Reactome events place these steps in the cytosol - one is titled "N-HH moves from the cytosol to the extracellular region" - which is a compartment assignment in that model rather than an observation about the protein. GO:0005829 is defined as the part of the cytoplasm that does not contain organelles, so it is not merely imprecise here but wrong.
GO:0005829 cytosol	TAS Reactome:R-DME-209313	REMOVE	Summary: A cytosolic location taken from a Drosophila Reactome model that places Hh autocleavage, Rasp-mediated palmitoylation and Dispatched-dependent release in the cytosol. Reason: Hh is never exposed to the cytosol. The precursor carries a cleaved signal sequence and is translocated into the endoplasmic reticulum, where the Hint/Hog domain performs cleavage and cholesterol transfer; Rasp palmitoylates the new N terminus within the secretory pathway; and Dispatched then releases the lipidated product from the plasma membrane to the outside. The cached Drosophila Reactome events place these steps in the cytosol - one is titled "N-HH moves from the cytosol to the extracellular region" - which is a compartment assignment in that model rather than an observation about the protein. GO:0005829 is defined as the part of the cytoplasm that does not contain organelles, so it is not merely imprecise here but wrong.
GO:0005829 cytosol	TAS Reactome:R-DME-209357	REMOVE	Summary: A cytosolic location taken from a Drosophila Reactome model that places Hh autocleavage, Rasp-mediated palmitoylation and Dispatched-dependent release in the cytosol. Reason: Hh is never exposed to the cytosol. The precursor carries a cleaved signal sequence and is translocated into the endoplasmic reticulum, where the Hint/Hog domain performs cleavage and cholesterol transfer; Rasp palmitoylates the new N terminus within the secretory pathway; and Dispatched then releases the lipidated product from the plasma membrane to the outside. The cached Drosophila Reactome events place these steps in the cytosol - one is titled "N-HH moves from the cytosol to the extracellular region" - which is a compartment assignment in that model rather than an observation about the protein. GO:0005829 is defined as the part of the cytoplasm that does not contain organelles, so it is not merely imprecise here but wrong.
GO:0005886 plasma membrane	EXP PMID:12586063 Cholesterol modification of hedgehog is required for traffic...	KEEP AS NON CORE	Summary: Cholesterol-modified Hh assembles into large punctate structures that are apically sorted and retained at the cell membrane; UniProt records the N-product as a lipid-anchored cell-membrane protein on the strength of this work. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Membrane tethering of the producing cell is a genuine and mechanistically important state of the mature ligand, and the same non-core call was made on the human orthologue review. Supporting Evidence: PMID:12586063 We demonstrate that cholesterol modification of Hedgehog is responsible for its assembly in large punctate structures and apical sorting through the activity of the sterol-sensing domain-containing Dispatched protein.
GO:0005886 plasma membrane	IDA PMID:17484784 Quantitative analysis of Hedgehog gradient formation using a...	KEEP AS NON CORE	Summary: Imaging of induced Hh-GFP detects the ligand at the apical and basolateral surfaces of target cells as well as in intracellular particles. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Supporting Evidence: PMID:17484784 The localization of Hh in these cells suggests that Hh normally moves across both apical and basolateral regions of the target cells.
GO:0005886 plasma membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: The UniProt subcellular-location keyword mapping records the lipid-anchored N-product at the cell membrane. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Unlike the nucleus and cytoplasm keywords on the same entry, this one rests on direct observation of the lipidated product rather than on an RNA localisation.
GO:0007224 smoothened signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: Pathway participation propagated from PAINT node PTN001726121, the broadest-seeded row at that node, spanning fly, zebrafish, chicken, mouse and the three human ligands. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. The family review assesses this node as SOUND, and Drosophila hh appearing among its seeds reflects the fly experimental annotations that helped place it.
GO:0007224 smoothened signaling pathway	IDA PMID:10409506 Mutants of cubitus interruptus that are independent of PKA r...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Mutants of cubitus interruptus that are independent of PKA regulation are independent of hedgehog signaling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:11486055 Skinny hedgehog, an acyltransferase required for palmitoylat...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:11495917 The fused protein kinase regulates Hedgehog-stimulated trans...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "The fused protein kinase regulates Hedgehog-stimulated transcriptional activation in Drosophila Schneider 2 cells.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:11934882 Hedgehog-stimulated phosphorylation of the kinesin-related p...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog-stimulated phosphorylation of the kinesin-related protein Costal2 is mediated by the serine/threonine kinase fused.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:14523402 Stability and association of Smoothened, Costal2 and Fused w...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:14636583 Hedgehog signal transduction via Smoothened association with...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:15598741 Extensive phosphorylation of Smoothened in Hedgehog pathway ...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Extensive phosphorylation of Smoothened in Hedgehog pathway activation.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:15616566 Hedgehog signalling activity of Smoothened requires phosphor...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:15691767 Hedgehog-regulated Costal2-kinase complexes control phosphor...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:16423832 Smoothened regulates activator and repressor functions of He...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:17960137 Hedgehog regulates smoothened activity by inducing a conform...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog regulates smoothened activity by inducing a conformational switch.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:20412775 The long-range activity of Hedgehog is regulated in the apic...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "The long-range activity of Hedgehog is regulated in the apical extracellular space by the glypican Dally and the hydrolase Notum.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Transduction of the Hedgehog signal through the dimerization of Fused and the nuclear translocation of Cubitus interruptus.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:21844892 As one of main morphogens during metazoan development, the graded Hh signal is transduced across the plasma membrane by Smoothened (Smo) through the differential phosphorylation of its cytoplasmic tail, leading to pathway activation and the differential expression of target genes.
GO:0007224 smoothened signaling pathway	IDA PMID:21852395 The Hedgehog-induced Smoothened conformational switch assemb...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "The Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:21852395 Here, we show that Hh-induced Smo conformational change recruits Costal2 (Cos2)/Fused (Fu) and promotes Fu kinase domain dimerization.
GO:0007224 smoothened signaling pathway	IDA PMID:22223683 The extracellular loops of Smoothened play a regulatory role...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "The extracellular loops of Smoothened play a regulatory role in control of Hedgehog pathway activation.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:22223683 We provide in vitro and in vivo evidence that EC1 cysteine mutation induces significant Hh-independent Smo signaling, triggering a level of pathway activation similar to that of a maximal Hh response in Drosophila and mammalian systems.
GO:0007224 smoothened signaling pathway	IDA PMID:22306085 Distinct phosphorylations on kinesin costal-2 mediate differ...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Distinct phosphorylations on kinesin costal-2 mediate differential hedgehog signaling strength.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:22537496 By using a Smo phospho-specific antibody, we demonstrate that Smo is differentially phosphorylated at three clusters of serine residues in response to levels of Hh activity.
GO:0007224 smoothened signaling pathway	IDA PMID:24985345 Hedgehog induces formation of PKA-Smoothened complexes to pr...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog induces formation of PKA-Smoothened complexes to promote Smoothened phosphorylation and pathway activation.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:24985345 Hedgehog (Hh) is a secreted glycoprotein that binds its receptor Patched to activate the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor-like protein Smoothened (Smo).
GO:0007224 smoothened signaling pathway	IDA PMID:25289679 Switch of PKA substrates from Cubitus interruptus to Smoothe...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:26271100 A Comparison of Ci/Gli Activity as Regulated by Sufu in Dros...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "A Comparison of Ci/Gli Activity as Regulated by Sufu in Drosophila and Mammalian Hedgehog Response.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:26271100 Some degree of Hh-induced transcriptional activation of Ci/Gli thus can occur independently of Sufu in both flies and mammals.
GO:0007224 smoothened signaling pathway	IDA PMID:26863604 PI(4)P Promotes Phosphorylation and Conformational Change of...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:26863604 In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo).
GO:0007224 smoothened signaling pathway	IDA PMID:27746045 Regulation of Smoothened Trafficking and Hedgehog Signaling ...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:27746045 We find that Hh stimulates Smo sumoylation by dissociating it from a desumoylation enzyme Ulp1.
GO:0007224 smoothened signaling pathway	IDA PMID:28360132 Dose-dependent transduction of Hedgehog relies on phosphoryl...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:29438012 Hedgehog reciprocally controls trafficking of Smo and Ptc th...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Hedgehog reciprocally controls trafficking of Smo and Ptc through the Smurf family of E3 ubiquitin ligases.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:29438012 Hedgehog (Hh) induces signaling by promoting the reciprocal trafficking of its receptor Patched (Ptc) and the signal transducer Smoothened (Smo), which is inhibited by Ptc, at the cell surface.
GO:0007224 smoothened signaling pathway	IDA PMID:30541874 Protein association changes in the Hedgehog signaling comple...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Protein association changes in the Hedgehog signaling complex mediate differential signaling strength.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:31279575 Phosphorylation of Ci/Gli by Fused Family Kinases Promotes H...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Phosphorylation of Ci/Gli by Fused Family Kinases Promotes Hedgehog Signaling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IDA PMID:36083801 High hedgehog signaling is transduced by a multikinase-depen...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "High hedgehog signaling is transduced by a multikinase-dependent switch controlling the apico-basal distribution of the GPCR smoothened.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:36083801 We provide evidence that HH promotes the stabilization of SMO by switching its fate after endocytosis toward recycling.
GO:0007224 smoothened signaling pathway	IDA PMID:36271509 Dose-dependent phosphorylation and activation of Hh pathway ...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Dose-dependent phosphorylation and activation of Hh pathway transcription factors.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:36271509 Here, we show that graded Hh induces a progressive increase in Ci phosphorylation at multiple Fused (Fu)/CK1 sites including a cluster located in the C-terminal Sufu-binding domain.
GO:0007224 smoothened signaling pathway	IDA PMID:39792672 Morphogen-induced kinase condensates transduce Hh signal by ...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IDA row (direct assay) is curated from "Morphogen-induced kinase condensates transduce Hh signal by allosterically activating Gli.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:39792672 Here we report that Hh induces phase separation of the fused (Fu)/Ulk family kinases to allosterically regulate Ci/Gli.
GO:0007224 smoothened signaling pathway	IGI PMID:11090136 Interactions with Costal2 and suppressor of fused regulate n...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "Interactions with Costal2 and suppressor of fused regulate nuclear translocation and activity of cubitus interruptus.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:11090136 In Drosophila, Hh acts by preventing the formation of a truncated repressor form of Cubitus interruptus (Ci) and stimulating the transcriptional activity of full-length Ci.
GO:0007224 smoothened signaling pathway	IGI PMID:1653906 Role of the Drosophila patched gene in positional signalling...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "Role of the Drosophila patched gene in positional signalling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IGI PMID:24931604 A rapid genome-wide microRNA screen identifies miR-14 as a m...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "A rapid genome-wide microRNA screen identifies miR-14 as a modulator of Hedgehog signaling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:24931604 We demonstrate that miR-14 is essential for maintaining the proper level of Hedgehog signaling activity by regulating its physiological target, hedgehog.
GO:0007224 smoothened signaling pathway	IGI PMID:8700230 smoothened encodes a receptor-like serpentine protein requir...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "smoothened encodes a receptor-like serpentine protein required for hedgehog signalling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IGI PMID:9874371 Hedgehog stimulates maturation of Cubitus interruptus into a...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IGI PMID:9874371 Hedgehog stimulates maturation of Cubitus interruptus into a...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IGI row (genetic interaction) is curated from "Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IMP PMID:15592457 Drosophila Smoothened phosphorylation sites essential for He...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IMP PMID:17671093 Fused-Costal2 protein complex regulates Hedgehog-induced Smo...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:17671093 In Drosophila, Hh-induced phosphorylation promotes Smo cell-surface accumulation and signaling activity; however, the mechanisms controlling Smo phosphorylation and cell-surface accumulation are still unknown.
GO:0007224 smoothened signaling pathway	IMP PMID:19850026 Regulation of smoothened by Drosophila G-protein-coupled rec...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Regulation of smoothened by Drosophila G-protein-coupled receptor kinases.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:19850026 In response to Hh binding to Ptc, Ptc-mediated repression of Smo is relieved, leading to Smo activation, surface accumulation, and downstream signaling.
GO:0007224 smoothened signaling pathway	IMP PMID:20435030 Dynamic phosphorylation of the kinesin Costal-2 in vivo reve...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Dynamic phosphorylation of the kinesin Costal-2 in vivo reveals requirement of fused kinase activity for all levels of hedgehog signalling.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IMP PMID:29522397 Proteolytic processing of palmitoylated Hedgehog peptides sp...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Proteolytic processing of palmitoylated Hedgehog peptides specifies the 3-4 intervein region of the Drosophila wing.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:29522397 Using wing development in Drosophila melanogaster as a model, we show that Hh relay and direct patterning of the 3-4 intervein region strictly depend on proteolytic removal of lipidated N-terminal membrane anchors.
GO:0007224 smoothened signaling pathway	IMP PMID:35037619 The NDNF-like factor Nord is a Hedgehog-induced extracellula...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:35037619 Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway.
GO:0007224 smoothened signaling pathway	IMP PMID:35573695 Dissection of the microRNA Network Regulating Hedgehog Signa...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence. Supporting Evidence: PMID:35573695 Importantly, through loss-of-function analysis, we found that endogenous miR-10 and miR-958 target fu and smo, respectively, whereas deletion of the other five miRNAs leads to altered expression of Hh signaling components, suggesting that these seven newly discovered miRNAs regulate Hh signaling in vivo.
GO:0007224 smoothened signaling pathway	IMP PMID:7577671 The Drosophila cubitus interruptus protein and its role in t...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "The Drosophila cubitus interruptus protein and its role in the wingless and hedgehog signal transduction pathways.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007224 smoothened signaling pathway	IMP PMID:8287482 Hedgehog is a signaling protein with a key role in patternin...	ACCEPT	Summary: Hh is the ligand whose binding to the Ptc-Ihog receptor complex initiates this pathway. This IMP row (mutant phenotype) is curated from "Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs.", one of the Drosophila studies in which Hh input is manipulated or supplied and pathway output is measured. Reason: Retained as a core pathway role. The ligand performs the receptor-binding step by which the smoothened signalling pathway is defined, so pathway participation here is direct rather than an indirect developmental consequence.
GO:0007267 cell-cell signaling	IEA GO_REF:0000002	MODIFY	Summary: An InterPro-to-GO mapping from the Hedgehog signalling domain and the Hint/Hog domain to the broad term cell-cell signalling. The direction is right but the mapping is far less specific than the pathway hh actually initiates, which is annotated here with direct evidence many times over. Reason: Cell-cell signalling is not wrong - Hh is the archetypal cell-cell signal of the fly embryo - but an InterPro signature that is diagnostic of a Hedgehog ligand supports the specific term. GO:0007224 smoothened signaling pathway is the term the same domains warrant and is already annotated to hh by IBA, IDA, IMP and IGI. Proposed replacements: smoothened signaling pathway
GO:0007346 regulation of mitotic cell cycle	IMP PMID:11279500 Hedgehog acts as a somatic stem cell factor in the Drosophil...	KEEP AS NON CORE	Summary: Hh acts on somatic stem cells in the adult ovary: these cells cannot proliferate as stem cells without Hh signalling, and excess signalling produces supernumerary stem cells. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. Supporting Evidence: PMID:11279500 These cells cannot proliferate as stem cells in the absence of Hh signalling, whereas excessive Hh signalling produces supernumerary stem cells.
GO:0007367 segment polarity determination	IEP PMID:8166882 Structure and expression of hedgehog, a Drosophila segment-p...	KEEP AS NON CORE	Summary: hh is a segment polarity gene, expressed in a series of segmental stripes from cellular blastoderm onwards; this IEP row is curated from the original structure-and-expression paper. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Segment polarity is the phenotype hh was named for and the reason it was cloned, so the annotation is unquestionably sound; it is nonetheless the embryo-level readout of the ligand's signalling activity. Supporting Evidence: PMID:8166882 Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication.
GO:0007367 segment polarity determination	IMP PMID:15930099 Hox-controlled reorganisation of intrasegmental patterning c...	KEEP AS NON CORE	Summary: Hox-controlled reorganisation of intrasegmental patterning shows Hh providing one of the specific segmental inputs that AbdB resets in abdominal segment 8. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Segment polarity is the phenotype hh was named for and the reason it was cloned, so the annotation is unquestionably sound; it is nonetheless the embryo-level readout of the ligand's signalling activity. Supporting Evidence: PMID:15930099 We show that the Hedgehog (Hh), Wingless (Wg) and Epidermal Growth Factor Receptor (Egfr) pathways provide specific inputs for posterior spiracle morphogenesis and act in a genetic network made of multiple and rapidly evolving Hox/signalling interplays.
GO:0007367 segment polarity determination	IMP PMID:7885476 The product of hedgehog autoproteolytic cleavage active in l...	KEEP AS NON CORE	Summary: Identification of the Hh autoproteolytic cleavage site and demonstration that the N-terminal product is the species active in local and long-range signalling in Drosophila patterning assays. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Segment polarity is the phenotype hh was named for and the reason it was cloned, so the annotation is unquestionably sound; it is nonetheless the embryo-level readout of the ligand's signalling activity. Supporting Evidence: PMID:7885476 We show here that the N product is the active species in both local and long-range signalling.
GO:0007367 segment polarity determination	IMP PMID:8287482 Hedgehog is a signaling protein with a key role in patternin...	KEEP AS NON CORE	Summary: Hh protein crosses parasegment borders and regulates patched and wingless expression in the embryonic epidermis. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Segment polarity is the phenotype hh was named for and the reason it was cloned, so the annotation is unquestionably sound; it is nonetheless the embryo-level readout of the ligand's signalling activity. Supporting Evidence: PMID:8287482 In the embryo, hedgehog regulation of patched apparently facilitates patched and wingless expression.
GO:0007367 segment polarity determination	IMP PMID:8700230 smoothened encodes a receptor-like serpentine protein requir...	KEEP AS NON CORE	Summary: smoothened is required for cells to respond to hedgehog during development of the embryonic segments; the genetic interaction places hh upstream in the segment polarity network. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Segment polarity is the phenotype hh was named for and the reason it was cloned, so the annotation is unquestionably sound; it is nonetheless the embryo-level readout of the ligand's signalling activity. Supporting Evidence: PMID:8700230 Here we show that the segment-polarity gene smoothened is required for the response of cells to hedgehog signalling during the development of both the embryonic segments and imaginal discs.
GO:0007386 compartment pattern specification	TAS PMID:11253649 Sticking together and sorting things out: adhesion as a forc...	KEEP AS NON CORE	Summary: Compartment pattern specification attributed to hh in a review of differential adhesion and cell sorting during development. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Hh signalling from the posterior compartment does organise pattern across the compartment boundary, so the term is sound, but the citation is a general review rather than primary evidence.
GO:0007418 ventral midline development	IMP PMID:16467357 Determination of cell fate along the anteroposterior axis of...	KEEP AS NON CORE	Summary: Midline cell fates are determined in the daughter cells, where a combination of repression by Wingless and activation by Hedgehog induces lethal of scute and then Engrailed. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:16467357 After the precursors divide, a combination of repression by Wingless and activation by Hedgehog induces expression of the proneural gene lethal of scute in the most anterior midline daughter cells of the neighbouring posterior segment.
GO:0007427 epithelial cell migration, open tracheal system	IMP PMID:11290298 Hedgehog signaling patterns the tracheal branches.	KEEP AS NON CORE	Summary: Hh is expressed in stripes abutting the anterior border of the tracheal placodes and patterns the branches; migration of tracheal cells is disrupted in hh mutant embryos. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:11290298 Hh is expressed in segmental stripes abutting the anterior border of the tracheal placodes.
GO:0007440 foregut morphogenesis	TAS PMID:10512197 Developmental genetics of the Drosophila gut: specification ...	KEEP AS NON CORE	Summary: Foregut morphogenesis attributed to hh in a developmental-genetics review of gut primordium specification and regionalisation. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0007442 hindgut morphogenesis	IMP PMID:11231061 Regulation of pattern formation in the Drosophila hindgut by...	KEEP AS NON CORE	Summary: hh is expressed in the prospective rectum, requires wg for its activation there, and is in turn required for dpp expression in the adjacent large intestine and for development of its own expression domain. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:11231061 wg and hh are also necessary for the development of their own expression domains, anal pads, and rectum, respectively.
GO:0007446 imaginal disc growth	TAS PMID:14691557 How are the sizes of cells, organs, and bodies controlled?	KEEP AS NON CORE	Summary: Imaginal disc growth attributed to hh in a review of organ and body size control. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Hh is one of the growth-organising signals of the disc, but this row rests on a review rather than on a growth assay of hh mutants.
GO:0007458 progression of morphogenetic furrow involved in compound eye morphogenesis	IEP PMID:8252628 The segment polarity gene hedgehog is required for progressi...	KEEP AS NON CORE	Summary: hh expression posterior to the morphogenetic furrow is continuously required for the furrow to advance across the eye disc; the IGI rows record the interaction with decapentaplegic, hairy and scabrous in the same study. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Furrow progression is a particularly clean example of the pattern: the requirement is continuous and the ligand is diffusing forward, but what the term names is the movement of an epithelial wavefront, executed by the responding cells. Supporting Evidence: PMID:8252628 We show that hh expression posterior to the morphogenetic furrow is continuously required for its progression.
GO:0007458 progression of morphogenetic furrow involved in compound eye morphogenesis	IGI PMID:8252628 The segment polarity gene hedgehog is required for progressi...	KEEP AS NON CORE	Summary: hh expression posterior to the morphogenetic furrow is continuously required for the furrow to advance across the eye disc; the IGI rows record the interaction with decapentaplegic, hairy and scabrous in the same study. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Furrow progression is a particularly clean example of the pattern: the requirement is continuous and the ligand is diffusing forward, but what the term names is the movement of an epithelial wavefront, executed by the responding cells. Supporting Evidence: PMID:8252628 We show that hh expression posterior to the morphogenetic furrow is continuously required for its progression.
GO:0007458 progression of morphogenetic furrow involved in compound eye morphogenesis	IGI PMID:8252628 The segment polarity gene hedgehog is required for progressi...	KEEP AS NON CORE	Summary: hh expression posterior to the morphogenetic furrow is continuously required for the furrow to advance across the eye disc; the IGI rows record the interaction with decapentaplegic, hairy and scabrous in the same study. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Furrow progression is a particularly clean example of the pattern: the requirement is continuous and the ligand is diffusing forward, but what the term names is the movement of an epithelial wavefront, executed by the responding cells. Supporting Evidence: PMID:8252628 We show that hh expression posterior to the morphogenetic furrow is continuously required for its progression.
GO:0007458 progression of morphogenetic furrow involved in compound eye morphogenesis	IGI PMID:8252628 The segment polarity gene hedgehog is required for progressi...	KEEP AS NON CORE	Summary: hh expression posterior to the morphogenetic furrow is continuously required for the furrow to advance across the eye disc; the IGI rows record the interaction with decapentaplegic, hairy and scabrous in the same study. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Furrow progression is a particularly clean example of the pattern: the requirement is continuous and the ligand is diffusing forward, but what the term names is the movement of an epithelial wavefront, executed by the responding cells. Supporting Evidence: PMID:8252628 We show that hh expression posterior to the morphogenetic furrow is continuously required for its progression.
GO:0007458 progression of morphogenetic furrow involved in compound eye morphogenesis	IMP PMID:8252628 The segment polarity gene hedgehog is required for progressi...	KEEP AS NON CORE	Summary: hh expression posterior to the morphogenetic furrow is continuously required for the furrow to advance across the eye disc; the IGI rows record the interaction with decapentaplegic, hairy and scabrous in the same study. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Furrow progression is a particularly clean example of the pattern: the requirement is continuous and the ligand is diffusing forward, but what the term names is the movement of an epithelial wavefront, executed by the responding cells. Supporting Evidence: PMID:8252628 We show that hh expression posterior to the morphogenetic furrow is continuously required for its progression.
GO:0007473 wing disc proximal/distal pattern formation	TAS PMID:12717815 Pattern formation in the Drosophila wing: The development of...	KEEP AS NON CORE	Summary: Wing vein patterning along the proximal/distal axis attributed to hh in a review of vein development. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0007476 imaginal disc-derived wing morphogenesis	IMP PMID:8287482 Hedgehog is a signaling protein with a key role in patternin...	KEEP AS NON CORE	Summary: Hh crossing the anterior/posterior compartment border of the wing disc regulates patched and other anterior genes, and hh manipulation alters adult wing pattern. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:8287482 Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs.
GO:0007478 leg disc morphogenesis	TAS PMID:11494318 The development of the Drosophila genital disc.	KEEP AS NON CORE	Summary: Leg disc morphogenesis attributed to hh in a review of genital disc development, which compares the terminalia primordia with other imaginal discs. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The cited review is primarily about the genital disc, so it is a weak anchor for a leg-disc claim; the term itself is sound, since Hh organises the anterior/posterior axis of the leg disc as it does in the wing.
GO:0007487 analia development	TAS PMID:11494318 The development of the Drosophila genital disc.	KEEP AS NON CORE	Summary: Development of the analia from the anal primordium of the genital disc, in which hh marks the posterior compartment of each contributing abdominal segment. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0007506 gonadal mesoderm development	IMP PMID:9435287 Identification of genes controlling germ cell migration and ...	KEEP AS NON CORE	Summary: hh was recovered in a third-chromosome screen for mutations disrupting germ cell migration and embryonic gonad formation, many of which affect development of the gonadal mesoderm. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:9435287 Many of these genes are involved in the development of gonadal mesoderm, the tissue that associates with germ cells to form the embryonic gonad.
GO:0007507 heart development	IMP PMID:8660881 The wingless signaling pathway is directly involved in Droso...	KEEP AS NON CORE	Summary: hh mutants are defective in heart formation, and the epistasis analysis places wingless downstream of hedgehog in this requirement. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The route to the cardiac phenotype runs through wg, which makes this an especially indirect outcome of ligand activity. Supporting Evidence: PMID:8660881 Here, we show that wg is epistatic to hedgehog (hh), another secreted segmentation gene product, in its requirement for heart formation.
GO:0007507 heart development	TAS PMID:10973066 Genetics of heart development.	KEEP AS NON CORE	Summary: Heart development attributed to hh in a review of cardiac developmental genetics. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0008347 glial cell migration	IMP PMID:11804568 Temporal control of glial cell migration in the Drosophila e...	KEEP AS NON CORE	Summary: hh acts with gilgamesh, sine oculis and eyeless in the posterior eye disc to prevent precocious glial cell migration, and targeted Hh expression rescues the gish phenotype. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The responding glia notably do not use the canonical pathway here, which the authors state explicitly. Supporting Evidence: PMID:11804568 gish, sine oculis, eyeless, and hedgehog (hh) act in the posterior region of the eye disc to prevent precocious glial cell migration.
GO:0008354 primordial germ cell migration	IDA NOT PMID:19389345 Hedgehog does not guide migrating Drosophila germ cells.	KEEP AS NON CORE	Summary: A NOT annotation: this row asserts the absence of the function. A targeted re-examination, repeating the critical earlier experiments, found no support for Hh acting as a germ cell attractant in Drosophila, consistent with findings in zebrafish. Reason: The negation is well supported and should be retained; it is the strongest single piece of evidence on this question. Whether Hh guides migrating germ cells is contested in the primary literature, and GOA carries both sides: Deshpande and Schedl reported Hh-dependent germ cell migration and an hmgcr interaction, while Renault and colleagues repeated the critical experiments and found no direct role. FlyBase records the negative result as a NOT annotation on this same term. The rows are kept as non-core rather than removed or left undecided: hh mutants do show germ cell migration defects, but the best explanation for them is the gonadal-mesoderm route that is annotated separately, not a direct guidance activity of the ligand. Users of this term should read the positive and negated rows together. Supporting Evidence: PMID:19389345 In contrast to previously reported findings and consistent with findings in zebrafish our data do not support the notion that Hh has a direct role in the guidance of migrating germ cells in flies.
GO:0008354 primordial germ cell migration	IGI PMID:16256738 HMGCoA reductase potentiates hedgehog signaling in Drosophil...	KEEP AS NON CORE	Summary: A genetic interaction with dispatched, from the study reporting that Hmgcr promotes release or transport of Hh from the somatic gonadal precursor cells. Reason: Whether Hh guides migrating germ cells is contested in the primary literature, and GOA carries both sides: Deshpande and Schedl reported Hh-dependent germ cell migration and an hmgcr interaction, while Renault and colleagues repeated the critical experiments and found no direct role. FlyBase records the negative result as a NOT annotation on this same term. The rows are kept as non-core rather than removed or left undecided: hh mutants do show germ cell migration defects, but the best explanation for them is the gonadal-mesoderm route that is annotated separately, not a direct guidance activity of the ligand. Users of this term should read the positive and negated rows together. Supporting Evidence: PMID:16256738 These findings suggest that Hmgcr might orchestrate germ cell migration by promoting the release and/or transport of Hh from the SGPs.
GO:0008354 primordial germ cell migration	IGI PMID:16256738 HMGCoA reductase potentiates hedgehog signaling in Drosophil...	KEEP AS NON CORE	Summary: A genetic interaction with Hmgcr, from the same study, which reports germ cell migration defects in trans combinations between hmgcr and hh pathway mutations. Reason: Whether Hh guides migrating germ cells is contested in the primary literature, and GOA carries both sides: Deshpande and Schedl reported Hh-dependent germ cell migration and an hmgcr interaction, while Renault and colleagues repeated the critical experiments and found no direct role. FlyBase records the negative result as a NOT annotation on this same term. The rows are kept as non-core rather than removed or left undecided: hh mutants do show germ cell migration defects, but the best explanation for them is the gonadal-mesoderm route that is annotated separately, not a direct guidance activity of the ligand. Users of this term should read the positive and negated rows together. Supporting Evidence: PMID:16256738 Consistent with this model, there are substantial germ cell migration defects in trans combinations between hmgcr and mutations in different components of the hh pathway.
GO:0008354 primordial germ cell migration	IMP PMID:9435287 Identification of genes controlling germ cell migration and ...	KEEP AS NON CORE	Summary: hh was recovered in a mutagenesis screen for genes disrupting germ cell migration at some step of embryonic development. Reason: Whether Hh guides migrating germ cells is contested in the primary literature, and GOA carries both sides: Deshpande and Schedl reported Hh-dependent germ cell migration and an hmgcr interaction, while Renault and colleagues repeated the critical experiments and found no direct role. FlyBase records the negative result as a NOT annotation on this same term. The rows are kept as non-core rather than removed or left undecided: hh mutants do show germ cell migration defects, but the best explanation for them is the gonadal-mesoderm route that is annotated separately, not a direct guidance activity of the ligand. Users of this term should read the positive and negated rows together. In this screen many of the recovered genes act through the gonadal mesoderm rather than on the germ cells themselves. Supporting Evidence: PMID:9435287 Many of these genes are involved in the development of gonadal mesoderm, the tissue that associates with germ cells to form the embryonic gonad.
GO:0008544 epidermis development	TAS PMID:10837029 Tissue- and stage-specific modulation of Wingless signaling ...	KEEP AS NON CORE	Summary: Epidermis development attributed to hh in a study of stage-specific modulation of Wingless signalling in the embryonic epidermis. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0009880 embryonic pattern specification	IEP PMID:1394430 Secretion and localized transcription suggest a role in posi...	KEEP AS NON CORE	Summary: hh encodes a protein targeted to the secretory pathway, expressed coincidently with engrailed, and its expression both responds to and contributes to embryonic positional information. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:1394430 Expression of hedgehog thus functions in, and is sensitive to, positional signaling.
GO:0010468 regulation of gene expression	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Regulation of gene expression propagated from PAINT node PTN001726121. Hedgehog ligands do change target-gene expression in every clade seeded at that node, so the assertion descends correctly. Reason: The node placement is not the problem; the term is. The entity that performs the regulation is Cubitus interruptus (Ci/GLI), several steps downstream, while the ligand changes the rate at which the responding cell does it. GO:0007224, already annotated with direct evidence, says what the ligand does with far more precision and covers the same biology, so this row is kept for retrieval but must not be read as an independent activity of hh. The family review reaches the same conclusion; note that the human orthologue review records ACCEPT for the equivalent row, a divergence made deliberately here.
GO:0016015 morphogen activity	IDA PMID:20412775 The long-range activity of Hedgehog is regulated in the apic...	ACCEPT	Summary: Apical and basolateral pools of Hh are distinguished in the wing disc epithelium, and reducing apical Hh selectively changes activation of low-threshold, long-range target genes without affecting short-range high-threshold targets. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. Threshold-specific target responses to different ligand pools are exactly the observation the morphogen activity term is defined by. Supporting Evidence: PMID:20412775 Here, we show that interfering with the amount of apical Hh causes a dramatic change in the long-range activation of low-threshold Hh target genes, without similar effect on short-range, high-threshold targets.
GO:0016015 morphogen activity	IDA PMID:21844892 Transduction of the Hedgehog signal through the dimerization...	ACCEPT	Summary: Graded Hh produces graded downstream responses: Smo phosphorylation is translated into Fused dimerisation and Ci nuclear localisation in a dose-dependent manner. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. Supporting Evidence: PMID:21844892 Here we present a model of the cell response to a Hh gradient by translating Smo phosphorylation information to Fu dimerization and Cubitus interruptus (Ci) nuclear localization information.
GO:0016015 morphogen activity	IDA PMID:22537496 Hh-induced Smoothened conformational switch is mediated by d...	ACCEPT	Summary: Smo is differentially phosphorylated at three serine clusters according to the level of Hh activity, so that distinct phosphorylation states mediate distinct Hh thresholds. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. Supporting Evidence: PMID:22537496 Thus, the differential phosphorylation of Smo mediates the thresholds of Hh activity.
GO:0016015 morphogen activity	IDA PMID:28825565 Cytoneme-mediated cell-cell contacts for Hedgehog reception.	ACCEPT	Summary: Hh is transported in vesicles along cytonemes from producing cells and received at membrane contact sites on cytonemes of receiving cells, a mechanism by which the gradient is formed. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. Supporting Evidence: PMID:28825565 Previously we demonstrated that Hedgehog (Hh) morphogen is transported via vesicles along cytonemes emanating from signal-producing cells to form a gradient in Drosophila epithelia.
GO:0016015 morphogen activity	IDA PMID:36271509 Dose-dependent phosphorylation and activation of Hh pathway ...	ACCEPT	Summary: Graded Hh drives a progressive, dose- and time-dependent increase in Ci phosphorylation at multiple Fused/CK1 sites, converting the ligand gradient into a Ci activity gradient. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. Supporting Evidence: PMID:36271509 Phosphorylation at the N-terminal, middle, and C-terminal Fu/CK1 sites occurred independently of one another and each increased progressively in response to increasing levels of Hh or increasing amounts of Hh exposure time.
GO:0016015 morphogen activity	IMP PMID:29522397 Proteolytic processing of palmitoylated Hedgehog peptides sp...	ACCEPT	Summary: Site-directed modification of the N-terminal Hh processing site eliminated the entire 3-4 intervein region of the wing, and additional removal of the N-palmitate restored it, showing that release of the lipidated anchors sets which patterning functions the ligand can perform at a distance. Reason: Retained as a core molecular function. Drosophila Hh is the canonical morphogen of the fly: target genes with different activation thresholds respond to different ligand concentrations across the anterior compartment, and the downstream Smo and Ci phosphorylation states scale with the amount and duration of Hh exposure. This row is also the clearest fly demonstration that lipidation state, not just ligand amount, governs range. Supporting Evidence: PMID:29522397 Hence, palmitoylated membrane anchors restrict morphogen spread until site-specific processing switches membrane-bound Hh into bioactive forms with specific patterning functions.
GO:0016335 morphogenesis of larval imaginal disc epithelium	IMP PMID:16236766 Developmental analysis and squamous morphogenesis of the per...	KEEP AS NON CORE	Summary: Morphogenesis of the squamous peripodial epithelium of wing, leg and eye discs, analysed for compartmental organisation, proliferation and lineage. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0016539 intein-mediated protein splicing	IEA GO_REF:0000002	REMOVE	Summary: An InterPro-to-GO mapping from the Hint/intein-like domain signature to intein-mediated protein splicing. The Hedgehog C-terminal domain is structurally homologous to intein splicing regions, but it does not splice: it performs a single cleavage in which the thioester intermediate is resolved by cholesterol, and the two products separate. Reason: GO:0016539 is defined as excision of an internal sequence followed by joining of the N- and C-terminal exteins by a normal peptide bond. Hedgehog does not ligate anything - the N-terminal signalling domain leaves with cholesterol esterified to its new C terminus, and the C-terminal domain is discarded. The homology that motivates the mapping is real and was described in the structure of the Drosophila autoprocessing domain, but homology to a splicing region is not splicing. The same REMOVE call was made on the human orthologue review, and GO:0016540 protein autoprocessing, already annotated here, is the correct term. Supporting Evidence: PMID:9335337 Aspects of sequence, structure, and reaction mechanism are conserved between Hh-C17 and the self-splicing regions of inteins, permitting reconstruction of a plausible evolutionary history of Hh-C and the inteins.
GO:0016540 protein autoprocessing	IDA PMID:7885476 The product of hedgehog autoproteolytic cleavage active in l...	ACCEPT	Summary: Identification of the Hh autoproteolytic cleavage site and demonstration that the N-terminal product generated by self-cleavage is the biologically active species. Reason: Retained as a core process. The precursor is its own processing enzyme: no separate protease is required, and the reaction is performed by the C-terminal Hint/Hog domain of the same polypeptide. This is one of only two genuinely catalytic activities the gene product has. Supporting Evidence: PMID:7885476 In a process that is critical for full biological activity, the hedgehog protein (Hh) undergoes autoproteolysis to generate two biochemically distinct products, an 18K amino-terminal fragment, N, and a 25K carboxy-terminal fragment, C (ref. 16); mutations that block autoproteolysis impair Hh function.
GO:0016540 protein autoprocessing	IDA PMID:9335337 Crystal structure of a Hedgehog autoprocessing domain: homol...	ACCEPT	Summary: Crystal structure of the Drosophila Hedgehog autoprocessing domain, which identified the active-site residues of the reaction. Reason: Retained as a core process. The precursor is its own processing enzyme: no separate protease is required, and the reaction is performed by the C-terminal Hint/Hog domain of the same polypeptide. This is one of only two genuinely catalytic activities the gene product has. This is structural evidence on the fly protein itself rather than a transfer from a vertebrate orthologue. Supporting Evidence: PMID:9335337 The approximately 25 kDa carboxy-terminal domain of Drosophila Hedgehog protein (Hh-C) possesses an autoprocessing activity that results in an intramolecular cleavage of full-length Hedgehog protein and covalent attachment of a cholesterol moiety to the newly generated amino-terminal fragment.
GO:0016540 protein autoprocessing	IEA GO_REF:0000002	ACCEPT	Summary: An InterPro-to-GO mapping from the Hedgehog/Hint autoprocessing domain signature to protein autoprocessing. Unlike the intein-splicing mapping from a neighbouring signature, this one states what the domain actually does. Reason: Retained as a core process. The precursor is its own processing enzyme: no separate protease is required, and the reaction is performed by the C-terminal Hint/Hog domain of the same polypeptide. This is one of only two genuinely catalytic activities the gene product has. An electronic annotation that lands on the right term is worth keeping alongside the experimental rows.
GO:0016540 protein autoprocessing	IMP PMID:9335337 Crystal structure of a Hedgehog autoprocessing domain: homol...	ACCEPT	Summary: Site-directed mutagenesis of the residues identified in the Drosophila autoprocessing domain structure, probing their role in the reaction; UniProt records T326A as greatly reducing autoprocessing and H329A as abolishing it. Reason: Retained as a core process. The precursor is its own processing enzyme: no separate protease is required, and the reaction is performed by the C-terminal Hint/Hog domain of the same polypeptide. This is one of only two genuinely catalytic activities the gene product has. Supporting Evidence: PMID:9335337 Residues in the Hh-C17 active site have been identified, and their role in Hedgehog autoprocessing probed by site-directed mutagenesis.
GO:0016540 protein autoprocessing	ISS GO_REF:0000024	ACCEPT	Summary: Curator-judged sequence-similarity transfer from mouse Shh (UniProtKB:Q62226) for the autoprocessing process term. Reason: Retained as a core process. The precursor is its own processing enzyme: no separate protease is required, and the reaction is performed by the C-terminal Hint/Hog domain of the same polypeptide. This is one of only two genuinely catalytic activities the gene product has. The transfer is safe: the chemistry is family-defining and, unusually for an ISS row, the target has its own direct structural and mutational evidence for the same claim.
GO:0030139 endocytic vesicle	IDA PMID:18198278 Patched, the receptor of Hedgehog, is a lipoprotein receptor...	KEEP AS NON CORE	Summary: Hh is detected in the endocytic compartment in the context of Patched acting as a lipoprotein receptor and internalising lipophorin particles. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Supporting Evidence: PMID:18198278 Interestingly, we also show that Patched (Ptc), the Hh receptor, is a lipoprotein receptor; Ptc actively internalizes Lp into the endocytic compartment in a Hh-independent manner and physically interacts with Lp.
GO:0030154 cell differentiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: A rule-based electronic annotation assigning the broad term cell differentiation. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The term is so general that it adds little beyond the specific developmental terms already present, but it is not wrong.
GO:0031410 cytoplasmic vesicle	IDA PMID:12586063 Cholesterol modification of hedgehog is required for traffic...	KEEP AS NON CORE	Summary: Cholesterol-modified Hh assembles into large punctate vesicular structures that are apically sorted in the embryonic epithelium. Reason: Kept, but as a non-core location. This compartment is part of the route the ligand takes to or from its site of action rather than the place where its receptor-binding activity is executed, which is the extracellular region. Supporting Evidence: PMID:12586063 We demonstrate that cholesterol modification of Hedgehog is responsible for its assembly in large punctate structures and apical sorting through the activity of the sterol-sensing domain-containing Dispatched protein.
GO:0034111 negative regulation of homotypic cell-cell adhesion	IDA PMID:31209108 The Drosophila Hedgehog receptor component Interference hedg...	KEEP AS NON CORE	Summary: Ihog and Boi engage in calcium-independent trans-homophilic interactions at cell-cell contacts, and Hh competes for the same surface of the first fibronectin repeat, so ligand binding reduces Ihog-mediated adhesion. Reason: Unusually for a downstream term, this one does reflect a direct action of the ligand: Hh competes for the Ihog surface rather than acting through the pathway. It is kept as non-core because it is a consequence of the same receptor-binding event that GO:0005113 already records, and because the adhesive function belongs to Ihog. Supporting Evidence: PMID:31209108 We further demonstrate that Hh interferes with Ihog-mediated homophilic interactions by competing for Ihog binding.
GO:0035154 terminal cell fate specification, open tracheal system	IMP PMID:24931604 A rapid genome-wide microRNA screen identifies miR-14 as a m...	KEEP AS NON CORE	Summary: Terminal cell fate in the tracheal system, from the genome-wide microRNA screen that identified hedgehog as the physiological target of miR-14. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:24931604 We demonstrate that miR-14 is essential for maintaining the proper level of Hedgehog signaling activity by regulating its physiological target, hedgehog.
GO:0035215 genital disc development	IMP PMID:15893978 Allocation and specification of the genital disc precursor c...	KEEP AS NON CORE	Summary: Allocation and specification of the genital disc precursor cells, analysed through embryonic patterning mutants including hh. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates.
GO:0035217 labial disc development	IMP PMID:15680366 Homeotic proboscipedia function modulates hedgehog-mediated ...	KEEP AS NON CORE	Summary: The labial-to-leg transformation of proboscipedia mutants requires hedgehog activity and involves morphogenetic reorganisation of the labial disc. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:15680366 This transformation requires hedgehog activity, and involves a morphogenetic reorganization of the labial imaginal disc.
GO:0035222 wing disc pattern formation	IDA PMID:20412775 The long-range activity of Hedgehog is regulated in the apic...	KEEP AS NON CORE	Summary: Apical Hh levels, set by the glypican Dally and the hydrolase Notum, determine long-range activation of low-threshold target genes in the wing disc. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. The patterning outcome is downstream of the morphogen activity annotated separately from the same study. Supporting Evidence: PMID:20412775 We provide genetic evidence that the glypican Dally upregulates apical Hh levels, and that the release of Dally by the hydrolase Notum promotes apical Hh long-range activity.
GO:0035224 genital disc anterior/posterior pattern formation	IEP PMID:8798147 Expression patterns of developmental genes reveal segment an...	KEEP AS NON CORE	Summary: engrailed and hedgehog expression was used to locate the posterior compartments of abdominal segments 8 to 10 in the genital discs, defining their anterior/posterior organisation. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. This IEP row rests on expression pattern rather than on a perturbation of hh. Supporting Evidence: PMID:8798147 engrailed (en) and hedgehog (hh) were used to locate posterior compartments in A8-A10, while cubitus interrupts (ci) localized the anterior compartments for each segment
GO:0035231 cytoneme assembly	IMP PMID:10367889 Cytonemes: cellular processes that project to the principal ...	KEEP AS NON CORE	Summary: Cytonemes are actin-based projections from wing disc cells towards the anterior/posterior signalling centre where Hh is produced; later work established that Hh is transported along cytonemes and received at cytoneme contact sites. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Assembly of the protrusion is done by the cytoskeleton of the cell that extends it, so hh is an input to this process rather than a participant in it; the annotation is kept because Hh availability does shape cytoneme behaviour, as the later cytoneme work in this reference set shows. Supporting Evidence: PMID:28825565 Here, we demonstrate that cytonemes protruding from Hh-receiving cells contribute to Hh gradient formation.
GO:0035232 germ cell attraction	TAS PMID:12814944 Cell migration and programmed cell death of Drosophila germ ...	REMOVE	Summary: Germ cell attraction by Hh, taken from a 2003 review of Drosophila germ cell migration. This is the strongest form of the contested claim - that Hh is a germ cell attractant - and it is the form that was directly tested and not supported. Reason: A later study repeated the critical experiments and specifically tested whether Hh is a germ cell attractant in flies, concluding that it is not; FlyBase itself records a NOT annotation for the related primordial germ cell migration term on the strength of that work. The evidence here is a traceable author statement in a review that predates the refutation, which is the weakest kind of support for the strongest version of the claim. The broader migration rows are kept as non-core because hh mutants do have migration defects; this attraction-specific term is not. Supporting Evidence: PMID:19389345 We therefore repeated several critical experiments and carried out further experiments to test specifically whether Hh is a germ cell attractant in flies.
GO:0035277 spiracle morphogenesis, open tracheal system	IMP PMID:15930099 Hox-controlled reorganisation of intrasegmental patterning c...	KEEP AS NON CORE	Summary: Posterior spiracle morphogenesis in abdominal segment 8 requires Hh alongside Wingless and EGFR inputs, reorganised under Abdominal-B control. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Supporting Evidence: PMID:15930099 We show that the Hedgehog (Hh), Wingless (Wg) and Epidermal Growth Factor Receptor (Egfr) pathways provide specific inputs for posterior spiracle morphogenesis and act in a genetic network made of multiple and rapidly evolving Hox/signalling interplays.
GO:0035288 anterior head segmentation	TAS PMID:15382142 The evolution of arthropod segmentation mechanisms.	KEEP AS NON CORE	Summary: Segmentation of the anterior head region attributed to hh in a comparative review of arthropod segmentation mechanisms. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. hh is a segment polarity gene and acts in all three regions, so the term is sound; the evidence is a review rather than a fly perturbation experiment.
GO:0035289 posterior head segmentation	TAS PMID:15382142 The evolution of arthropod segmentation mechanisms.	KEEP AS NON CORE	Summary: Segmentation of the posterior head region attributed to hh in a comparative review of arthropod segmentation mechanisms. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. hh is a segment polarity gene and acts in all three regions, so the term is sound; the evidence is a review rather than a fly perturbation experiment.
GO:0035290 trunk segmentation	TAS PMID:15382142 The evolution of arthropod segmentation mechanisms.	KEEP AS NON CORE	Summary: Segmentation of the trunk region attributed to hh in a comparative review of arthropod segmentation mechanisms. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. hh is a segment polarity gene and acts in all three regions, so the term is sound; the evidence is a review rather than a fly perturbation experiment.
GO:0045861 negative regulation of proteolysis	IDA PMID:9215627 Proteolysis that is inhibited by hedgehog targets Cubitus in...	KEEP AS NON CORE	Summary: Hh inhibits the proteolytic processing of Cubitus interruptus that would otherwise generate the nuclear repressor form. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. The proteolysis is carried out by the proteasome acting on a phosphorylated, Slimb-targeted Ci, within the responding cell; Hh sets whether it happens. Supporting Evidence: PMID:9215627 Hh inhibits proteolysis of Ci, and we suggest that this inhibition leads to the observed patterns of expression of key target genes at the compartment border.
GO:0048066 developmental pigmentation	TAS PMID:12957543 Evolution in black and white: genetic control of pigment pat...	UNDECIDED	Summary: Developmental pigmentation attributed to hh in a review of the genetic control of Drosophila pigment patterns. Neither the local publication cache nor PubMed holds an abstract for this reference, so the basis of the statement cannot be inspected. Reason: The standing rule is to mark an annotation UNDECIDED when the relevant publication cannot be accessed, and that is the situation here: the cached record contains only the title and identifiers, and PubMed returns no abstract for this reference either. Abdominal pigmentation is prepatterned by segment polarity genes, so a role for hh is plausible, but plausibility is not a substitute for the evidence, and no other reference in this set addresses pigmentation. Resolving this needs the full text of the review or a primary pigmentation study.
GO:0048099 anterior/posterior lineage restriction, imaginal disc	TAS PMID:10625531 Subdividing cell populations in the developing limbs of Dros...	UNDECIDED	Summary: Anterior/posterior lineage restriction in imaginal discs attributed to hh in a paper on whether wing veins and leg segments define units of growth control. Neither the local publication cache nor PubMed holds an abstract for this reference. Reason: Marked undecided because the cited publication cannot be inspected: the cached record holds only the title and identifiers, and PubMed returns no abstract. Hedgehog signalling across the anterior/posterior boundary is certainly involved in maintaining compartment organisation, so this is likely to be sound, but the specific claim about lineage restriction cannot be checked against the cited evidence, and it is a distinct claim from the patterning term annotated from the same paper.
GO:0048100 wing disc anterior/posterior pattern formation	TAS PMID:10625531 Subdividing cell populations in the developing limbs of Dros...	KEEP AS NON CORE	Summary: Wing disc anterior/posterior pattern formation, cited to a paper on units of growth control in the developing limbs. The cached record for this reference holds no abstract, but the term is independently supported by the other three references annotated to it. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Anterior/posterior patterning of the wing disc is the textbook readout of Hh signalling and is supported here by several independent references, so the term is not in doubt even though one of the four citations has no retrievable abstract.
GO:0048100 wing disc anterior/posterior pattern formation	TAS PMID:11253649 Sticking together and sorting things out: adhesion as a forc...	KEEP AS NON CORE	Summary: Wing disc anterior/posterior pattern formation, cited to a review of differential adhesion and cell sorting in development. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Anterior/posterior patterning of the wing disc is the textbook readout of Hh signalling and is supported here by several independent references, so the term is not in doubt even though one of the four citations has no retrievable abstract.
GO:0048100 wing disc anterior/posterior pattern formation	TAS PMID:12717815 Pattern formation in the Drosophila wing: The development of...	KEEP AS NON CORE	Summary: Wing disc anterior/posterior pattern formation, cited to a review of vein pattern formation in the Drosophila wing. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Anterior/posterior patterning of the wing disc is the textbook readout of Hh signalling and is supported here by several independent references, so the term is not in doubt even though one of the four citations has no retrievable abstract.
GO:0048100 wing disc anterior/posterior pattern formation	TAS PMID:15104233 Regulation of Hedgehog signaling: a complex story.	KEEP AS NON CORE	Summary: Wing disc anterior/posterior pattern formation, cited to a review of Hedgehog pathway regulation, which describes Ci regulation in response to a graded concentration of Hh ligand. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Anterior/posterior patterning of the wing disc is the textbook readout of Hh signalling and is supported here by several independent references, so the term is not in doubt even though one of the four citations has no retrievable abstract. Supporting Evidence: PMID:15104233 Ci is regulated through communication of the membrane proteins Patched (Ptc) and Smoothened (Smo) to the intracellular Hedgehog Signaling Complex (HSC) in response to a graded concentration of Hh ligand.
GO:0048731 system development	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: A rule-based electronic annotation assigning the broad term system development. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. It is a correct but very general parent of the specific developmental terms already annotated.
GO:0140853 cholesterol-protein transferase activity	ISS GO_REF:0000024	ACCEPT	Summary: Cholesterol-protein transferase activity, transferred by curator judgement from mouse Shh (UniProtKB:Q62226). This is the reaction the Drosophila Hint/Hog domain performs: cleavage coupled to esterification of cholesterol onto Gly257, the new C terminus of the N-product. Reason: Retained as a core molecular function, and one of only two genuine catalytic activities of the gene product. The ISS transfer is safe here because the fly protein has its own direct evidence: the crystal structure of the Drosophila autoprocessing domain, the D303A mutation that abolishes cholesterol transfer, and the cholesterol glycine ester recorded at Gly257 by mass spectrometry. The family review assesses this term as family-wide, and the Hedgehog module places the reaction on the ligand itself rather than on an external enzyme. Supporting Evidence: PMID:9335337 The approximately 25 kDa carboxy-terminal domain of Drosophila Hedgehog protein (Hh-C) possesses an autoprocessing activity that results in an intramolecular cleavage of full-length Hedgehog protein and covalent attachment of a cholesterol moiety to the newly generated amino-terminal fragment.
GO:0160108 animal gross anatomical part developmental process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: A rule-based electronic annotation assigning the broad term animal gross anatomical part developmental process. Reason: Kept, but as a non-core annotation. Drosophila hh is a single ligand with one biochemical output, and the many tissue phenotypes recorded for it are downstream outcomes of that one ligand activity in different developmental contexts. The annotation is biologically sound and worth keeping for phenotype retrieval, but core status is reserved for the ligand's own activities: autoproteolysis with cholesterol transfer, Patched binding, and the smoothened signalling pathway it initiates. Very general, but consistent with the many specific organ and appendage terms annotated from fly experiments.
GO:2000010 positive regulation of protein localization to cell surface	IDA PMID:19088085 PP4 and PP2A regulate Hedgehog signaling by controlling Smo ...	KEEP AS NON CORE	Summary: Hh induces accumulation of Smoothened at the cell surface, a step regulated by PP4 acting on Smo phosphorylation. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. The protein whose localisation changes is Smo, and the trafficking is carried out by the responding cell's machinery. Supporting Evidence: PMID:19088085 We further find that PP4 regulates the Hh-induced Smo cell-surface accumulation.
GO:2000274 regulation of epithelial cell migration, open tracheal system	IMP PMID:24651658 Hedgehog is a positive regulator of FGF signalling during em...	KEEP AS NON CORE	Summary: Hh positively regulates Branchless/FGF levels during embryonic tracheal development and so modulates tracheal cell migration non-autonomously, acting through the transcription factor Stripe. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. The migrating cells respond to FGF; Hh acts upstream of its expression. Supporting Evidence: PMID:24651658 We propose that Hh modulates embryonic cell migration by participating in the spatio-temporal regulation of bnl expression in a permissive mode.
GO:2000495 regulation of cell proliferation involved in compound eye morphogenesis	IMP PMID:17559828 Suppression of Hedgehog signaling by Cul3 ligases in prolife...	KEEP AS NON CORE	Summary: Hh regulates the population of interommatidial cells during retinal development, with Cullin3 acting to limit the response by degrading Ci. Reason: Kept, but as a non-core annotation. The event recorded here happens inside the responding cell, several steps downstream of ligand binding, and is performed by pathway components rather than by Hh itself; Hh is the input that changes its rate. Retaining it as non-core records the causal link without implying that the ligand executes the step. Supporting Evidence: PMID:17559828 This process is manifested in controlling cell proliferation during Drosophila retinal development.

hh

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

FlyBase

FlyBase gene description for hh (DROME)

📚 Additional Documentation

Notes

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