shha encodes zebrafish Sonic hedgehog a, the principal Hedgehog-family morphogen of the fish embryo and the product of the classical sonic you (syu) mutant locus. It is a 418-residue secreted precursor with a signal peptide, an N-terminal signalling domain and a C-terminal Hint domain. In the endoplasmic reticulum the Hint domain autocleaves the precursor and, acting as an intramolecular cholesterol-protein transferase, esterifies cholesterol onto the new C terminus of the N-terminal fragment; Hhat then palmitoylates its N terminus. The dually lipidated N-product (ShhNp) is tethered to the producing cell membrane and released with the help of Dispatched and Scube proteins. It binds Patched (ptch1/ptch2) on responding cells, relieving Patched repression of Smoothened and switching Gli transcription factors to their activator forms. shha is expressed in the embryonic shield, notochord, medial floor plate, ventral forebrain and zona limitans intrathalamica, pectoral fin bud mesenchyme, anterior endoderm, pharyngeal and tooth epithelium, retina and epicardium. Graded or short-range Shha signalling from these sources specifies lateral floor plate and motor neurons, ventral spinal cord precursor domains and oligodendrocyte lineage cells, slow-twitch muscle and muscle pioneers within somites, anteroposterior polarity of the pectoral fin, posterior otic identity, prethalamus/thalamus, adenohypophysis, endocrine pancreas, arterial endothelium, cardiomyocyte number, craniofacial cartilage, teeth, swimbladder, cloaca and the timing of retinal neurogenesis and cell-cycle exit. Unlike mouse Shh, shha is not required for medial floor plate induction, which is Nodal-dependent in zebrafish, and many of its roles are shared redundantly with the co-ortholog shhb (tiggy-winkle hedgehog). Heterozygous loss produces age-related cone photoreceptor loss, and epicardial shha is a short-range mitogen for myocardium during heart development and regeneration.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The Shh precursor and its processed N-product transit the Golgi, where HHAT palmitoylation and DISP/SCUBE-dependent export are completed (UniProt SubCell; transferred from human SHH). Reason: Golgi transit is a real but transient biosynthetic location for a secreted morphogen, not the site where shha acts. Retained as a non-core lifecycle location; the active location is the extracellular region. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The Shh precursor and its processed N-product transit the Golgi, where HHAT palmitoylation and DISP/SCUBE-dependent export are completed (UniProt SubCell; transferred from human SHH). Reason: Golgi transit is a real but transient biosynthetic location for a secreted morphogen, not the site where shha acts. Retained as a non-core lifecycle location; the active location is the extracellular region. |
| GO:0001708 cell fate specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference that Hedgehog ligands specify cell fates; the zebrafish gene is itself one of the experimental sources for the node. Reason: Graded Shh specifies ventral neural, slow-muscle and other fates in zebrafish. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 Graded Hedgehog (Hh) signaling patterns the spinal cord dorsoventral axis by inducing and positioning distinct precursor domains, each of which gives rise to a different type of neuron. PMID:10642786 while such signalling is essential for slow myocyte differentiation, the loss of activity of one signal, Sonic hedgehog, can be partially compensated for by other Hedgehog family proteins |
| GO:0001708 cell fate specification | IMP PMID:15229178 Fgf3 signaling from the ventral diencephalon is required for... | KEEP AS NON CORE | Summary: Ectopic shha induces adenohypophyseal cells in placodal regions of fgf3 mutants, showing Shh can specify pituitary fate independently of Fgf3. Reason: Gain-of-function evidence for fate specification in the pituitary placode. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15229178 it is able to induce adenohypophyseal cells in ectopic placodal regions of fgf3 mutants, indicating that Fgf3 does not act via Shh, and that Shh can act independently of Fgf3 |
| GO:0001756 somitogenesis | IGI PMID:18326814 Calcitonin receptor-like receptor guides arterial differenti... | MODIFY | Summary: Somitic expression of crlr, needed for arterial differentiation, is under shha control (shha mutant x crlr morphant interaction). Reason: syu mutants form somites normally but mis-pattern them (U- rather than V-shaped, no horizontal myoseptum, loss of slow muscle and muscle pioneers). GO:0001756 somitogenesis is defined as the formation of the segmental mesodermal clusters, which is Shh-independent; the phenotype is a defect in the subsequent patterning of the somite. GO:0061053 somite development (already carried by mouse Shh by IMP) is the accurate term. Essence sound, term too specific in the wrong direction. Here the readout is somitic crlr expression, again a patterning/gene-expression phenotype within formed somites. Proposed replacements: somite development Supporting Evidence: PMID:18326814 genetic and biochemical evidences indicate that somitic crlr expression is under the control of sonic hedgehog |
| GO:0001756 somitogenesis | IMP PMID:9655820 Sonic hedgehog is not required for the induction of medial f... | MODIFY | Summary: syu (shha) deletion mutants show defects in somite patterning. Reason: syu mutants form somites normally but mis-pattern them (U- rather than V-shaped, no horizontal myoseptum, loss of slow muscle and muscle pioneers). GO:0001756 somitogenesis is defined as the formation of the segmental mesodermal clusters, which is Shh-independent; the phenotype is a defect in the subsequent patterning of the somite. GO:0061053 somite development (already carried by mouse Shh by IMP) is the accurate term. Essence sound, term too specific in the wrong direction. Proposed replacements: somite development Supporting Evidence: PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. |
| GO:0001756 somitogenesis | IMP PMID:9655820 Sonic hedgehog is not required for the induction of medial f... | MODIFY | Summary: syu (shha) deletion mutants show defects in somite patterning. Reason: syu mutants form somites normally but mis-pattern them (U- rather than V-shaped, no horizontal myoseptum, loss of slow muscle and muscle pioneers). GO:0001756 somitogenesis is defined as the formation of the segmental mesodermal clusters, which is Shh-independent; the phenotype is a defect in the subsequent patterning of the somite. GO:0061053 somite development (already carried by mouse Shh by IMP) is the accurate term. Essence sound, term too specific in the wrong direction. Proposed replacements: somite development Supporting Evidence: PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. |
| GO:0001839 neural plate morphogenesis | IMP PMID:16502420 Hedgehog signalling controls zebrafish neural keel morphogen... | KEEP AS NON CORE | Summary: Hh loss- and gain-of-function alter neural keel morphogenesis through level-dependent effects on neurogenesis. Reason: Neural keel morphogenesis is the zebrafish equivalent of neural plate/tube morphogenesis; the effect is indirect via neurogenesis and PCP. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16502420 Through the analyses of Hh loss- and gain-of-function phenotypes, we found that Hh signalling controls the neural keel morphogenesis. |
| GO:0001947 heart looping | IDA PMID:9334285 Left-right pattern of cardiac BMP4 may drive asymmetry of th... | KEEP AS NON CORE | Summary: shh mRNA injection raises cardiac bmp4 diffusely and prevents directional jogging and looping of the heart tube. Reason: Gain-of-function only (ectopic ubiquitous shh); it shows Shh can perturb looping via BMP4 but does not by itself show an endogenous requirement. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9334285 Raising BMP4 diffusely throughout the heart, via sonic hedgehog injection, or the blocking of its action by injection of a dominant negative BMP4 receptor, prevent directional jogging or looping. |
| GO:0004175 endopeptidase activity | ISS GO_REF:0000024 | MODIFY | Summary: Endopeptidase activity transferred from mouse Shh, capturing the Hint-domain self-cleavage of the precursor. Reason: The precursor cleavage is a cholesterolysis: the Hint domain performs an N-S acyl shift and cholesterol, not water, attacks the thioester, so the reaction (RHEA:59504) is a cholesterol-protein transferase reaction rather than peptide-bond hydrolysis. GO now has the precise term GO:0140853, already annotated to shha by ISS; the generic endopeptidase term should be replaced by it, as was done in the human SHH review. Proposed replacements: cholesterol-protein transferase activity Supporting Evidence: PMID:8824192 Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. |
| GO:0005113 patched binding | IBA GO_REF:0000033 | ACCEPT | Summary: Patched binding by the ShhN ligand, inferred by PAINT at node PTN001726121 from fly hh and mammalian Shh/Ihh/Dhh experimental data. Reason: Binding of the lipidated N-product to Patched is the mechanism by which every Hedgehog ligand relieves Patched repression of Smoothened. In zebrafish the Hh-responsive genes ptc1/ptc2 mark direct target cells and all shha phenotypes are phenocopied by smo (smu) mutants. This is the core molecular function of the ligand. Supporting Evidence: PMID:12606279 We show that the Hh responsive genes ptc1 and nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube at this time, indicating that these cells are directly receiving Hh signals. PMID:16626681 Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Calcium binding by the ShhN signalling domain, inferred by PAINT; UniProt annotates the Ca2+ and Zn2+ sites (residues 89-131) by similarity to mouse. Reason: Calcium and zinc coordination stabilise the ShhN fold and one calcium-mediated surface forms part of the Patched interface, so the annotation is correct. It is a structural property that enables the receptor-binding activity rather than a function in its own right, so it is kept as non-core. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places the secreted, extracellular action of the Hedgehog N-product at the family node PTN001726121; zebrafish Shh acts on neighbouring tissues as a secreted, mostly short-range signal. Reason: The processed ShhN ligand is released and acts on Patched-expressing target cells; mosaic analyses in zebrafish show it acting non-cell-autonomously over short range. This is the core active location. Supporting Evidence: PMID:15253932 By performing mosaic analysis, we demonstrate that Shh directs these events as a short-range signal within the neural retina. PMID:12606279 We show that the Hh responsive genes ptc1 and nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube at this time, indicating that these cells are directly receiving Hh signals. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Endoplasmic reticulum: the compartment in which the Shh precursor undergoes autocleavage coupled to cholesterol transfer (transferred from human SHH). Reason: The ER is where the C-terminal Hint domain performs the cholesterolysis that generates ShhN, so it is the active location of the precursor's own molecular function. Retained as core for the autoprocessing activity unit. Supporting Evidence: PMID:8824192 During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. PMID:7583153 Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endoplasmic reticulum membrane, from UniProt SubCell / human SHH transfer; the precursor co-localises with HHAT in the ER before export. Reason: The precursor is a lumenal/secretory protein that autoprocesses in the ER; membrane association is via lipid anchors and HHAT proximity. The ER as a compartment (GO:0005783) is retained as the core site of autoprocessing; the membrane term is kept as a non-core biosynthetic location. Supporting Evidence: PMID:8824192 During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endoplasmic reticulum membrane, from UniProt SubCell / human SHH transfer; the precursor co-localises with HHAT in the ER before export. Reason: The precursor is a lumenal/secretory protein that autoprocesses in the ER; membrane association is via lipid anchors and HHAT proximity. The ER as a compartment (GO:0005783) is retained as the core site of autoprocessing; the membrane term is kept as a non-core biosynthetic location. Supporting Evidence: PMID:8824192 During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The Shh precursor and its processed N-product transit the Golgi, where HHAT palmitoylation and DISP/SCUBE-dependent export are completed (UniProt SubCell; transferred from human SHH). Reason: Golgi transit is a real but transient biosynthetic location for a secreted morphogen, not the site where shha acts. Retained as a non-core lifecycle location; the active location is the extracellular region. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane of the producing cell, where dually lipidated ShhNp is tethered before DISP/SCUBE-mediated release (UniProt SubCell; from mouse Shh). Reason: Membrane tethering of the lipidated N-product is a genuine step in ligand presentation and release, and juxtacrine signalling from this location is plausible, but the annotated receptor-binding activity is exercised on responding cells, i.e. extracellularly. Kept as a non-core location. Supporting Evidence: PMID:16626681 Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Plasma membrane of the producing cell, where dually lipidated ShhNp is tethered before DISP/SCUBE-mediated release (UniProt SubCell; from mouse Shh). Reason: Membrane tethering of the lipidated N-product is a genuine step in ligand presentation and release, and juxtacrine signalling from this location is plausible, but the annotated receptor-binding activity is exercised on responding cells, i.e. extracellularly. Kept as a non-core location. Supporting Evidence: PMID:16626681 Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. |
| GO:0007224 smoothened signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference that the Hedgehog ligand family initiates smoothened signalling; the shha mutant (sonic you) is the founding zebrafish Hh-pathway mutant. Reason: shha encodes the principal zebrafish Hedgehog ligand. Loss of shha (syu) reproduces a subset of the smoothened (smu) phenotype and Hh target genes (ptc1, nkx2.2) are lost in syu mutants. Core process. Supporting Evidence: PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. PMID:12606279 We show that the Hh responsive genes ptc1 and nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube at this time, indicating that these cells are directly receiving Hh signals. |
| GO:0007224 smoothened signaling pathway | IGI PMID:16626681 Scube2 mediates Hedgehog signalling in the zebrafish embryo. | ACCEPT | Summary: Genetic interaction between shha and scube2 (you) in Hh signal transduction; Scube2 acts upstream of Smoothened at the level of ligand receipt/release. Reason: Abstract-only cache, but the biology is unambiguous: shha is the ligand whose signalling scube2 facilitates. Core process. Supporting Evidence: PMID:16626681 Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. |
| GO:0007224 smoothened signaling pathway | IGI PMID:22609552 Scube activity is necessary for Hedgehog signal transduction... | ACCEPT | Summary: Genetic interaction of shha with the scube1/2/3 morphants; combined Scube loss phenocopies complete loss of Hh signal transduction. Reason: Abstract-only cache; Scube proteins mediate release of the lipidated ShhN, so shha is the ligand in this epistasis. Core process. Supporting Evidence: PMID:22609552 Knocking down the function of all three scube genes simultaneously phenocopies a complete loss of HH signal transduction in the embryo, revealing that Scube signaling is essential for HH signal transduction in vivo. |
| GO:0007267 cell-cell signaling | IEA GO_REF:0000002 | ACCEPT | Summary: Cell-cell signalling from the InterPro Hedgehog signalling domain (IPR000320/IPR001657). Reason: Generic but correct: shha is a secreted intercellular signal. The more specific smoothened signalling pathway terms are also present, so this broad IEA is acceptable as-is. Supporting Evidence: PMID:15253932 By performing mosaic analysis, we demonstrate that Shh directs these events as a short-range signal within the neural retina. |
| GO:0007368 determination of left/right symmetry | IDA PMID:9334285 Left-right pattern of cardiac BMP4 may drive asymmetry of th... | KEEP AS NON CORE | Summary: Ubiquitous shh injection abolishes the left-predominant bmp4 pattern and directional jogging/looping. Reason: Evidence is overexpression disrupting asymmetry rather than loss of shha; endogenous shha is not asymmetrically expressed in zebrafish. Retained with this caveat because the curator read the full text. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9334285 Raising BMP4 diffusely throughout the heart, via sonic hedgehog injection, or the blocking of its action by injection of a dominant negative BMP4 receptor, prevent directional jogging or looping. |
| GO:0007389 pattern specification process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'pattern specification process' from sequence/family features. Reason: Shh is the archetypal vertebrate morphogen; D/V neural tube and A/P fin patterning are experimentally annotated below. Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0007399 nervous system development | IMP PMID:13129844 Hedgehog signaling is directly required for the development ... | KEEP AS NON CORE | Summary: Hh pathway mutants including syu lack dorsal root ganglion neurons and ngn1 expression in DRG precursors. Reason: Peripheral (DRG) neurogenesis requires Hh signalling directly in precursors. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:13129844 Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. |
| GO:0007411 axon guidance | IMP PMID:19846707 Muscle contractions guide rohon-beard peripheral sensory axo... | MARK AS OVER ANNOTATED | Summary: Rohon-Beard sensory axon pathfinding defects in shha (syu) mutants. Reason: The paper's own conclusion is that the RB axon defects in syu, yot and smu mutants arise because these mutants lack early muscle contraction, and that mechanical force from contracting muscle guides the axons; embedding wild-type embryos in agarose phenocopies the defect. shha is therefore several steps upstream (muscle pioneer/slow muscle specification) and does not itself act as a guidance cue here. Not wrong under acts_upstream_of_or_within, but it is an indirect phenotype rather than participation in axon guidance. Supporting Evidence: PMID:19846707 To further test the role of muscle development or function in RB axon guidance, we examined three mutants in the sonic hedgehog signaling pathway, which is required for proper muscle development. PMID:19846707 This work suggests that the mechanical forces generated by muscle contractions are necessary for proper sensory axon pathfinding in vivo. |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'central nervous system development' from sequence/family features. Reason: Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0007417 central nervous system development | IMP PMID:13129844 Hedgehog signaling is directly required for the development ... | KEEP AS NON CORE | Summary: CNS development annotation citing the dorsal root ganglion paper. Reason: The cached abstract concerns DRG neurons, which are peripheral; the CNS claim cannot be verified from it (full text not cached), but shha's CNS roles (floor plate, motor neurons, spinal precursor domains) are firmly established by other cited papers, so the annotation is kept with those added as support. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10694427 These data indicate that shh, expressed in the notochord and/or the MFP cells, induces the formation of LFP cells. PMID:15539490 Graded Hedgehog (Hh) signaling patterns the spinal cord dorsoventral axis by inducing and positioning distinct precursor domains, each of which gives rise to a different type of neuron. |
| GO:0007420 brain development | IMP PMID:12843251 Genetic analysis of the roles of Hh, FGF8, and nodal signali... | KEEP AS NON CORE | Summary: syu mutants lose the pretectal catecholaminergic cluster and have reduced, disorganised ventral diencephalic DA clusters at 3 dpf. Reason: Note the paper's headline is that Shh is NOT required for the earliest diencephalic DA neurons; the requirement is for later pretectal/retinal catecholaminergic cells. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12843251 Later in development (3 dpf), analysis of th expression reveals that the pretectal cluster of catecholaminergic neurons is reduced or even absent in syu mutants |
| GO:0007507 heart development | IMP PMID:28513431 Dissection of zebrafish shha function using site-specific ta... | KEEP AS NON CORE | Summary: Epicardium-specific conditional knockout of shha (Zwitch allele) causes cardiac oedema, a thin myocardial wall and fewer cardiomyocytes. Reason: High-quality conditional loss-of-function; epicardial Shha is a short-range mitogen for adjacent myocardium. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:28513431 The epi-KO embryos had a thinner myocardial wall (Figure 4D) and significantly fewer cardiomyocytes (Figure 4E). These findings indicate that epicardium-derived Shha plays a crucial role in zebrafish heart development. |
| GO:0007517 muscle organ development | IMP PMID:17046741 Hedgehog acts directly on the zebrafish dermomyotome to prom... | KEEP AS NON CORE | Summary: Hh signalling acts directly on dermomyotomal pax3/7 precursors to promote fast-muscle growth. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17046741 Hh also positively regulates the growth of embryonic fast muscle. |
| GO:0008015 blood circulation | IMP PMID:9007249 Mutations affecting the cardiovascular system and other inte... | MARK AS OVER ANNOTATED | Summary: Circulation defects recorded for the syu (sonic you) genotype in the 1996 Tuebingen internal-organ screen. Reason: The cached abstract is the screen overview and does not mention syu; the circulatory phenotype of shha mutants is explained mechanistically by the loss of arterial identity downstream of Shh-Vegf-Notch (PMID:12110173). 'Blood circulation' is a physiological outcome, not a process shha participates in; the informative annotations are the arterial/vascular ones. Supporting Evidence: PMID:12110173 Loss of Vegf or Shh results in loss of arterial identity, while exogenous expression of these factors causes ectopic expression of arterial markers. |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:15891769 Shh directs cell-cycle exit by activating p57Kip2 in the zeb... | KEEP AS NON CORE | Summary: Shh drives cell-cycle exit of retinal progenitors by inducing p57Kip2; shh mutants over-proliferate and fail to differentiate. Reason: A well-dissected, tissue-specific anti-proliferative output of Shh signalling. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15891769 Here, we show that Shh activity is required for cell-cycle exit of progenitor cells in the zebrafish retina, and that this effect is mediated by p57Kip2. |
| GO:0009888 tissue development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning prediction of 'tissue development' from sequence/family features. Reason: Biologically true for shha but so general that it conveys nothing beyond the many specific developmental annotations already present; flagged as over-annotation. |
| GO:0009952 anterior/posterior pattern specification | IGI PMID:12588855 Hedgehog signalling is required for correct anteroposterior ... | KEEP AS NON CORE | Summary: shha and shhb (twhh) act redundantly to impose posterior identity on the otic vesicle. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12588855 By using double mutants and antisense morpholino analysis, we also show that both Sonic hedgehog and Tiggy-winkle hedgehog are involved in anteroposterior patterning of the zebrafish otic vesicle. |
| GO:0009952 anterior/posterior pattern specification | IMP PMID:10518498 Transient establishment of anteroposterior polarity in the z... | KEEP AS NON CORE | Summary: syu mutants show that Shh is needed for some aspects of pectoral fin bud A/P polarity and for maintenance of others. Reason: Classic ZPA-type role of Shh in the paired appendage. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10518498 We show that Shh is required for the establishment of some aspects of anteroposterior polarity, while other aspects of anteroposterior polarity are established independently of Shh, and only later come to depend on Shh for their maintenance. |
| GO:0009953 dorsal/ventral pattern formation | IMP PMID:15539490 Spatial and temporal regulation of ventral spinal cord precu... | KEEP AS NON CORE | Summary: Graded Hh signalling sets and maintains ventral spinal cord precursor domains. Reason: The canonical D/V patterning role of Shh in the neural tube. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 Graded Hedgehog (Hh) signaling patterns the spinal cord dorsoventral axis by inducing and positioning distinct precursor domains, each of which gives rise to a different type of neuron. |
| GO:0010001 glial cell differentiation | IMP PMID:15253932 Sonic hedgehog, secreted by amacrine cells, acts as a short-... | KEEP AS NON CORE | Summary: Differentiation of inner and outer nuclear layer cell types (including glia) and retinal lamination depend on shh. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15253932 We also show that differentiation of cell types found in the inner and outer nuclear layers, as well as lamination of the retina, depends on shh. |
| GO:0010002 cardioblast differentiation | IMP PMID:18842815 Hedgehog signaling plays a cell-autonomous role in maximizin... | KEEP AS NON CORE | Summary: Hh signalling promotes cardiomyocyte formation; shha mRNA injection increases atrial cardiomyocyte number, smo loss reduces it. Reason: The shha-specific evidence in this paper is gain-of-function (mRNA injection); loss-of-function was done with smo and ptc alleles. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:18842815 Here, we show that Hh signaling promotes cardiomyocyte formation in zebrafish. Reduced Hh signaling creates a cardiomyocyte deficit, and increased Hh signaling creates a surplus. PMID:18842815 Quantification of cells in the cardiac chambers of shh-injected embryos revealed an increased number of atrial cardiomyocytes |
| GO:0010468 regulation of gene expression | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference that Hedgehog ligands regulate target-gene expression (via Gli transcription factors in responding cells). Reason: Shh signalling changes Gli activator/repressor output and thereby the transcription of ptc1, nkx2.2, olig2 and many other targets; in zebrafish these responses are lost in syu mutants and induced by ectopic shha. The term is broad but the PAINT curator placed it at the family node deliberately, and it correctly describes the downstream consequence of the core activity. Supporting Evidence: PMID:12606279 Consistent with a direct role for Hh signaling in pituitary induction and patterning, overexpression of Shh results in expanded adenohypophyseal expression of lim3, expansion of nk2.2 into the posterior adenohypophysis, and an increase in Prolactin- and Somatolactin-secreting cells. PMID:12606279 We show that the Hh responsive genes ptc1 and nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube at this time, indicating that these cells are directly receiving Hh signals. |
| GO:0010468 regulation of gene expression | IDA PMID:10021344 A Drosophila doublesex-related gene, terra, is involved in s... | ACCEPT | Summary: shh overexpression reduces expression of the dsx-related gene terra in the presomitic mesoderm (IDA by mRNA injection). Reason: A single-target overexpression readout, consistent with Hh signalling regulating target-gene expression. Accepted alongside the IBA for the same term (the two rows are judged together); on its own it adds little. Supporting Evidence: PMID:10021344 In vivo, terra expression is reduced by hedgehog but enhanced by BMP signals. |
| GO:0016539 intein-mediated protein splicing | IEA GO_REF:0000002 | REMOVE | Summary: InterPro IPR006141 (Intein_N) mapping: the Hedgehog Hint domain is homologous to the N-terminal intein splicing domain. Reason: Homology is real but the process is not: intein-mediated protein splicing excises an internal segment and re-ligates the flanking exteins with a peptide bond. Hedgehog Hint domains perform only the first half-reaction (N-S acyl shift) and resolve the thioester with cholesterol, producing two separate products; no splicing occurs. Demonstrably wrong InterPro2GO propagation, as also concluded in the human SHH review. Supporting Evidence: PMID:8824192 Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. |
| GO:0016540 protein autoprocessing | IEA GO_REF:0000002 | ACCEPT | Summary: Autoprocessing of the Shh precursor into ShhN and ShhC by the Hint domain. Reason: The Hint (Hedgehog/intein) domain autocleaves the precursor; zebrafish Shh is shown to undergo autoproteolytic processing in vivo. Core process of the precursor, executed by the cholesterol-protein transferase activity. Supporting Evidence: PMID:7583153 Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. PMID:8824192 During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. |
| GO:0016540 protein autoprocessing | ISS GO_REF:0000024 | ACCEPT | Summary: Autoprocessing of the Shh precursor into ShhN and ShhC by the Hint domain. Reason: The Hint (Hedgehog/intein) domain autocleaves the precursor; zebrafish Shh is shown to undergo autoproteolytic processing in vivo. Core process of the precursor, executed by the cholesterol-protein transferase activity. Supporting Evidence: PMID:7583153 Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. PMID:8824192 During biosynthesis, Hh undergoes an autocleavage reaction, mediated by its carboxyl-terminal domain, that produces a lipid-modified amino-terminal fragment responsible for all known Hh signaling activity. |
| GO:0021508 floor plate formation | IGI PMID:12508225 Cyclops-independent floor plate differentiation in zebrafish... | KEEP AS NON CORE | Summary: Late, Cyclops-independent differentiation of medial floor plate cells in cyc mutants depends on an intact Hh pathway. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12508225 This late differentiation is restricted to the hindbrain and spinal cord and depends on an intact Hedgehog (Hh) signalling pathway. |
| GO:0021508 floor plate formation | IMP PMID:10694427 Two distinct cell populations in the floor plate of the zebr... | KEEP AS NON CORE | Summary: shha (syu) is required to induce lateral floor plate cells but not the medial floor plate. Reason: Note the nuance: in zebrafish, unlike mouse, Shh is dispensable for medial floor plate induction (Nodal/Cyclops-dependent) and required for the lateral floor plate. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10694427 These data indicate that shh, expressed in the notochord and/or the MFP cells, induces the formation of LFP cells. PMID:10694427 It has been shown previously that in the zebrafish shh is required for the induction of LFP cells, but not for the development of MFP cells. |
| GO:0021520 spinal cord motor neuron cell fate specification | IMP PMID:9242415 Temporal separation in the specification of primary and seco... | KEEP AS NON CORE | Summary: Primary motoneuron specification correlates with shh in gastrula axial mesoderm; secondary motoneurons need shh-expressing floor plate or notochord. Reason: This 1997 paper predates the identification of syu as shh and uses cyc/flh midline mutants, so its shha evidence is correlative; the requirement is confirmed genetically by the strong loss of primary motor neurons in cyc;syu double mutants (PMID:10694427), added as support. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9242415 primary motoneuronal specification depends on the presence of sonic hedgehog in gastrula axial mesoderm, the tissue that will give rise to the notochord PMID:10694427 The number of primary motor neurons is strongly reduced in cyc;syu double mutants, while almost normal in single mutants, suggesting that the two different pathways have overlapping functions in the induction of primary motor neurons. |
| GO:0021536 diencephalon development | IGI PMID:18358464 A novel role for zebrafish zic2a during forebrain developmen... | KEEP AS NON CORE | Summary: Prethalamic dlx2a expression is reduced in syu mutants and further lost when zic2a is also knocked down. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:18358464 dlx2a expression was reduced in the PT of both mutants, while expression in the telencephalon remained relatively normal |
| GO:0021984 adenohypophysis development | IDA PMID:12606279 Multiple roles for Hedgehog signaling in zebrafish pituitary... | KEEP AS NON CORE | Summary: Overexpression of Shh expands adenohypophyseal lim3/nk2.2 domains and hormone-secreting cell numbers. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12606279 Consistent with a direct role for Hh signaling in pituitary induction and patterning, overexpression of Shh results in expanded adenohypophyseal expression of lim3, expansion of nk2.2 into the posterior adenohypophysis, and an increase in Prolactin- and Somatolactin-secreting cells. |
| GO:0021984 adenohypophysis development | IMP PMID:12606279 Multiple roles for Hedgehog signaling in zebrafish pituitary... | KEEP AS NON CORE | Summary: Hh pathway mutants and cyclopamine show Hh signalling from neural ectoderm is required 10-15 hpf for adenohypophysis induction, when only shh is expressed. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12606279 We report that Hh signaling is necessary between 10 and 15 h of development for induction of the zebrafish adenohypophysis, a time when shh is expressed only in neural tissue. |
| GO:0021984 adenohypophysis development | IMP PMID:12606280 Adenohypophysis formation in the zebrafish and its dependenc... | KEEP AS NON CORE | Summary: Shh from the ventral diencephalon is required for induction, patterning and growth of the adenohypophysis (loss- and gain-of-function). Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12606280 Carrying out loss- and gain-of-function experiments, we show that Shh from the ventral diencephalon plays a crucial role during induction, patterning, and growth of the zebrafish adenohypophysis. |
| GO:0021986 habenula development | IMP PMID:27387288 Habenular Neurogenesis in Zebrafish Is Regulated by a Hedgeh... | KEEP AS NON CORE | Summary: shha(tbx392) mutants show strongly reduced habenular cxcr4b and brn3a expression; Shha is the main Hh ligand for habenular neurogenesis. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:27387288 we found that the expression of both cxcr4b and brn3a are strongly reduced in this context. These data suggest that Shha is the main Hedgehog ligand involved in habenular neurogenesis |
| GO:0030182 neuron differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'neuron differentiation' from sequence/family features. Reason: Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0030182 neuron differentiation | IMP PMID:12843251 Genetic analysis of the roles of Hh, FGF8, and nodal signali... | KEEP AS NON CORE | Summary: syu mutants lack dat-expressing dopaminergic amacrine cells and pretectal catecholaminergic neurons. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12843251 In the retinae of both syu and smu mutants, dat -expressing amacrine cells are absent or reduced in number, indicating a defect in DA amacrine cell differentiation |
| GO:0030182 neuron differentiation | IMP PMID:16502420 Hedgehog signalling controls zebrafish neural keel morphogen... | KEEP AS NON CORE | Summary: Hh signalling has level-dependent effects on medial and lateral neurogenesis in the neural keel. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16502420 Hh signalling mainly controls keel morphogenesis by means of affecting both medial and lateral neurogenesis |
| GO:0030510 regulation of BMP signaling pathway | IDA PMID:9334285 Left-right pattern of cardiac BMP4 may drive asymmetry of th... | KEEP AS NON CORE | Summary: Ectopic shh raises BMP4 expression throughout the heart tube. Reason: Regulation of BMP signalling here means transcriptional induction of bmp4 by ectopic Shh; a downstream effect of the core signalling activity. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9334285 Raising BMP4 diffusely throughout the heart, via sonic hedgehog injection, or the blocking of its action by injection of a dominant negative BMP4 receptor, prevent directional jogging or looping. |
| GO:0030900 forebrain development | IMP PMID:16452095 Hedgehog signalling from the zona limitans intrathalamica or... | KEEP AS NON CORE | Summary: ZLI-derived shha (with twhh) patterns prethalamus and thalamus; shha morphants lose ptch1/dlx2a/dbx1a domains. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16452095 we show that shh and twhh display both unique and redundant functions during diencephalic patterning |
| GO:0030902 hindbrain development | IMP PMID:15281067 Hedgehog and Fgf signaling pathways regulate the development... | KEEP AS NON CORE | Summary: syu mutants show severe reduction of tphR-expressing serotonergic raphe neurons in the hindbrain. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15281067 serotonergic raphe neurons are absent in embryos lacking Hh activity confirming a conserved role for Hh signals in the induction of these cells |
| GO:0030917 midbrain-hindbrain boundary development | IMP PMID:28493069 Comparison of molecular marker expression in early zebrafish... | MARK AS OVER ANNOTATED | Summary: shha morpholino perturbed midbrain-hindbrain boundary morphology (30/30) in a marker survey of ethanol-sensitive signals. Reason: Morpholino-only evidence with no mutant corroboration, and the MHB molecular markers (fgf8a, pax2a, eng2b) were unaffected in shha morphants, so the morphological change is uninterpreted and possibly non-specific. syu mutants are not reported to have MHB defects elsewhere. Not clearly wrong, but weakly supported relative to the rest of the shha annotation set. Supporting Evidence: PMID:28493069 As shown here, Shh MO (Figure 5B) and fgf8a MO treatment perturbed MHB formation, both at the ratio of 30/30 (Figure 5C). PMID:28493069 Fgf8 expression in MHB was relatively normal in ethanol exposed embryos (Figure 6B), agrin morphants (Figure 6C) and shh morphants (Figure 6D). |
| GO:0030947 regulation of vascular endothelial growth factor receptor signaling pathway | IMP PMID:12110173 sonic hedgehog and vascular endothelial growth factor act up... | KEEP AS NON CORE | Summary: shh acts upstream of vegf, which acts upstream of Notch, to specify arterial endothelial fate; vegf mRNA rescues arterial differentiation in Shh-deficient embryos. Reason: Shh regulates VEGF signalling by inducing vegf expression in the somites; a downstream transcriptional consequence. Artery development (GO:0060840) would be an equally apt companion term. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12110173 We find that vascular endothelial growth factor (vegf) acts downstream of sonic hedgehog (shh) and upstream of the Notch pathway to determine arterial cell fate. |
| GO:0031016 pancreas development | IDA PMID:11553330 Hedgehog signaling pathway is essential for pancreas specifi... | KEEP AS NON CORE | Summary: Ubiquitous Hh pathway activation induces ectopic endodermal pdx-1 and supernumerary endocrine cells. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:11553330 Zebrafish embryos compromised in Hh signaling exhibit disruption in the expression of the pancreas-specifying homeobox gene pdx-1 and concomitantly show almost complete absence of the endocrine pancreas. |
| GO:0031016 pancreas development | IEP PMID:17289013 TALE-family homeodomain proteins regulate endodermal sonic h... | KEEP AS NON CORE | Summary: shh is expressed in anterior endoderm where it represses pancreatic gene expression; meis3/pbx4 act upstream of endodermal shh. Reason: Expression-pattern evidence only (IEP); the functional requirement is carried by the IMP rows from PMID:11553330 and PMID:11900460. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17289013 sonic hedgehog (shh) is expressed in anterior endoderm, where it is required to repress pancreas gene expression and to pattern the endoderm |
| GO:0031016 pancreas development | IMP PMID:11553330 Hedgehog signaling pathway is essential for pancreas specifi... | KEEP AS NON CORE | Summary: syu and other Hh pathway mutants lose pdx-1 expression and most of the endocrine pancreas. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:11553330 Zebrafish embryos compromised in Hh signaling exhibit disruption in the expression of the pancreas-specifying homeobox gene pdx-1 and concomitantly show almost complete absence of the endocrine pancreas. |
| GO:0031018 endocrine pancreas development | IDA PMID:11900460 Sonic hedgehog is required early in pancreatic islet develop... | KEEP AS NON CORE | Summary: Shh and pathway mutants show a requirement specific to the endocrine, not exocrine, pancreas; transient early Hh signalling during gastrulation is needed for islet differentiation. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:11900460 Genetic mutants of Shh and its signaling pathway establish this dependence as specific to endocrine, but not exocrine, pancreas. |
| GO:0031018 endocrine pancreas development | IMP PMID:11900460 Sonic hedgehog is required early in pancreatic islet develop... | KEEP AS NON CORE | Summary: Shh and pathway mutants show a requirement specific to the endocrine, not exocrine, pancreas; transient early Hh signalling during gastrulation is needed for islet differentiation. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:11900460 Genetic mutants of Shh and its signaling pathway establish this dependence as specific to endocrine, but not exocrine, pancreas. |
| GO:0031076 embryonic camera-type eye development | IMP PMID:15857917 Staggered cell-intrinsic timing of ath5 expression underlies... | KEEP AS NON CORE | Summary: Midline Shh signals before neurogenesis set the intrinsic neurogenic timer of retinal progenitors (ath5 wave). Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15857917 We provide evidence that midline Sonic hedgehog signals, acting before the onset of neurogenesis, are part of the mechanism that sets the neurogenic timer in these cells. |
| GO:0032835 glomerulus development | IMP PMID:10885753 The zebrafish floating head mutant demonstrates podocytes pl... | KEEP AS NON CORE | Summary: In syu (and flh, yot) mutants glomeruli differentiate at ectopic lateral positions; podocyte differentiation is unaffected. Reason: The effect is indirect: loss of midline/dorsal aorta signals mispositions the glomerulus without blocking podocyte differentiation. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10885753 In flh, syu, and yot mutants, glomeruli differentiate at ectopic lateral positions within the embryo and contain morphologically identifiable podocyte and endothelial cell types. PMID:10885753 Our results suggest that midline signals are required for proper glomerular morphogenesis but not for the differentiation of podocytes. |
| GO:0033339 pectoral fin development | IMP PMID:10518498 Transient establishment of anteroposterior polarity in the z... | KEEP AS NON CORE | Summary: syu mutants: Shh needed for apical ectodermal fold, fin bud growth and endoskeleton. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10518498 Finally, we show that Shh is required for normal development of the apical ectodermal fold, for growth of the fin bud, and for formation of the fin endoskeleton. |
| GO:0033339 pectoral fin development | IMP PMID:10976049 dackel acts in the ectoderm of the zebrafish pectoral fin bu... | KEEP AS NON CORE | Summary: Shh in fin mesenchyme acts with dackel to maintain apical fold fgf4/fgf8 signalling. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10976049 dak acts synergistically with Shh to induce fgf4 and fgf8 expression but independently of Shh in promoting apical fold morphogenesis. |
| GO:0033339 pectoral fin development | IMP PMID:10976049 dackel acts in the ectoderm of the zebrafish pectoral fin bu... | KEEP AS NON CORE | Summary: Shh in fin mesenchyme acts with dackel to maintain apical fold fgf4/fgf8 signalling. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10976049 dak acts synergistically with Shh to induce fgf4 and fgf8 expression but independently of Shh in promoting apical fold morphogenesis. |
| GO:0033339 pectoral fin development | IMP PMID:9007245 Genetic analysis of fin formation in the zebrafish, Danio re... | KEEP AS NON CORE | Summary: Tuebingen fin-formation screen; shh expression in posterior fin mesenchyme and pectoral fin mutants including syu. Reason: The abstract describes shh expression in dak mutants rather than the syu phenotype itself, but the pectoral fin defect of syu is confirmed in PMID:9655820 and PMID:10518498. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9007245 Expression of sonic hedgehog mRNA in the posterior mesenchyme of the pectoral fin bud is initiated in dak embryos, but not maintained. PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. |
| GO:0033339 pectoral fin development | IMP PMID:9655820 Sonic hedgehog is not required for the induction of medial f... | KEEP AS NON CORE | Summary: syu deletion mutants have defective pectoral fins. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. |
| GO:0033339 pectoral fin development | IMP PMID:9655820 Sonic hedgehog is not required for the induction of medial f... | KEEP AS NON CORE | Summary: syu deletion mutants have defective pectoral fins. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:9655820 Embryos mutant for a deletion of syu display defects in patterning of the somites, the lateral floor plate cells, the pectoral fins, the axons of motorneurons and the retinal ganglion cells. |
| GO:0033504 floor plate development | IMP PMID:10694427 Two distinct cell populations in the floor plate of the zebr... | KEEP AS NON CORE | Summary: syu mutants lack lateral floor plate cells; shh RNA injection expands LFP but not MFP. Reason: Same nuance as floor plate formation: the requirement is for the lateral, not the medial, floor plate population. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10694427 These data indicate that shh, expressed in the notochord and/or the MFP cells, induces the formation of LFP cells. PMID:9655820 In contrast to mouse embryos lacking Shh activity, syu mutant embryos do form medial floor plate cells and motorneurons. |
| GO:0033504 floor plate development | IMP PMID:10694427 Two distinct cell populations in the floor plate of the zebr... | KEEP AS NON CORE | Summary: syu mutants lack lateral floor plate cells; shh RNA injection expands LFP but not MFP. Reason: Same nuance as floor plate formation: the requirement is for the lateral, not the medial, floor plate population. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10694427 These data indicate that shh, expressed in the notochord and/or the MFP cells, induces the formation of LFP cells. PMID:9655820 In contrast to mouse embryos lacking Shh activity, syu mutant embryos do form medial floor plate cells and motorneurons. |
| GO:0033504 floor plate development | IMP PMID:10694427 Two distinct cell populations in the floor plate of the zebr... | KEEP AS NON CORE | Summary: syu mutants lack lateral floor plate cells; shh RNA injection expands LFP but not MFP. Reason: Same nuance as floor plate formation: the requirement is for the lateral, not the medial, floor plate population. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10694427 These data indicate that shh, expressed in the notochord and/or the MFP cells, induces the formation of LFP cells. PMID:9655820 In contrast to mouse embryos lacking Shh activity, syu mutant embryos do form medial floor plate cells and motorneurons. |
| GO:0035143 caudal fin morphogenesis | IMP PMID:17597528 Hedgehog signaling patterns the outgrowth of unpaired skelet... | KEEP AS NON CORE | Summary: The adult caudal fin primordium fails to form in syu and smu mutants; midline Shh acts without a ZPA-like domain. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17597528 GFP expression was strongly reduced or completely lost in the region of the ACFP of the two mutants, indicating that Shh signaling is required for normal patterning of the ACFP |
| GO:0035295 tube development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning prediction of 'tube development' from sequence/family features. Reason: Biologically true for shha but so general that it conveys nothing beyond the many specific developmental annotations already present; flagged as over-annotation. |
| GO:0042063 gliogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'gliogenesis' from sequence/family features. Reason: Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0042063 gliogenesis | IGI PMID:15539490 Spatial and temporal regulation of ventral spinal cord precu... | KEEP AS NON CORE | Summary: Hh sets, maintains and subdivides the olig2+ ventral precursor domain and subsequently specifies oligodendrocyte development. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 we provide evidence that these biases emerge from Hh acting over time to set, maintain, subdivide and enlarge the olig2+ precursor domain and subsequently specify oligodendrocyte development |
| GO:0042063 gliogenesis | IMP PMID:15539490 Spatial and temporal regulation of ventral spinal cord precu... | KEEP AS NON CORE | Summary: Hh sets, maintains and subdivides the olig2+ ventral precursor domain and subsequently specifies oligodendrocyte development. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 we provide evidence that these biases emerge from Hh acting over time to set, maintain, subdivide and enlarge the olig2+ precursor domain and subsequently specify oligodendrocyte development |
| GO:0042127 regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'regulation of cell population proliferation' from sequence/family features. Reason: Shh both promotes proliferation (cardiomyocytes, spinal precursors) and drives cell-cycle exit (retina), so the direction-neutral parent is apt. Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0042462 eye photoreceptor cell development | IMP PMID:15253932 Sonic hedgehog, secreted by amacrine cells, acts as a short-... | KEEP AS NON CORE | Summary: Photoreceptor (outer nuclear layer) differentiation depends on shh acting as a short-range signal from amacrine and ganglion cells. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15253932 We also show that differentiation of cell types found in the inner and outer nuclear layers, as well as lamination of the retina, depends on shh. |
| GO:0042462 eye photoreceptor cell development | IMP PMID:15891769 Shh directs cell-cycle exit by activating p57Kip2 in the zeb... | KEEP AS NON CORE | Summary: shh mutant retinal progenitors fail to exit the cell cycle and to differentiate. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15891769 In the absence of either shh or p57Kip2 activity, most of the retinal progenitor cells continue to proliferate and fail to differentiate. |
| GO:0042476 odontogenesis | IMP PMID:21118524 Hedgehog signaling is required at multiple stages of zebrafi... | KEEP AS NON CORE | Summary: shha(t4) mutants and shha (not shhb) morphants fail to initiate or complete pharyngeal tooth development; shha is the only Hh ligand in tooth germs. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:21118524 we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation |
| GO:0042476 odontogenesis | IMP PMID:21118524 Hedgehog signaling is required at multiple stages of zebrafi... | KEEP AS NON CORE | Summary: shha(t4) mutants and shha (not shhb) morphants fail to initiate or complete pharyngeal tooth development; shha is the only Hh ligand in tooth germs. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:21118524 we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation |
| GO:0042694 muscle cell fate specification | IMP PMID:10642786 Control of muscle cell-type specification in the zebrafish e... | KEEP AS NON CORE | Summary: Slow-twitch muscle and muscle pioneer specification require Hh; syu loss is partially compensated by other Hh ligands. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10642786 while such signalling is essential for slow myocyte differentiation, the loss of activity of one signal, Sonic hedgehog, can be partially compensated for by other Hedgehog family proteins |
| GO:0043010 camera-type eye development | IDA PMID:15728669 pitx3 defines an equivalence domain for lens and anterior pi... | KEEP AS NON CORE | Summary: shh overexpression blocks lens formation and converts lens precursors to pituitary character. Reason: Gain-of-function evidence; the endogenous eye roles are covered by the IMP rows on retinal differentiation. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15728669 overexpression of sonic hedgehog (shh) blocks lens formation, and derivatives of lens precursors express genes characteristic of pituitary cells |
| GO:0045165 cell fate commitment | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'cell fate commitment' from sequence/family features. Reason: Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:18502998 Age-related cone abnormalities in zebrafish with genetic les... | KEEP AS NON CORE | Summary: Aged syu heterozygotes, with reduced retinal shh mRNA, show regional cone loss and disordered cone mosaics. Reason: Adult heterozygote phenotype with a dosage-dependent, correlative link to shha; a plausible maintenance role but weaker than the embryonic evidence. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:18502998 Regions of cone loss and abnormal cone morphology were observed in the oldest syu(+/-) zebrafish, although no other retinal cell type was affected. PMID:18502998 Shh signaling may be required to maintain cone viability throughout life. |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:18502998 Age-related cone abnormalities in zebrafish with genetic les... | KEEP AS NON CORE | Summary: Aged syu heterozygotes, with reduced retinal shh mRNA, show regional cone loss and disordered cone mosaics. Reason: Adult heterozygote phenotype with a dosage-dependent, correlative link to shha; a plausible maintenance role but weaker than the embryonic evidence. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:18502998 Regions of cone loss and abnormal cone morphology were observed in the oldest syu(+/-) zebrafish, although no other retinal cell type was affected. PMID:18502998 Shh signaling may be required to maintain cone viability throughout life. |
| GO:0045880 positive regulation of smoothened signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of smoothened signalling, transferred from human SHH: the ligand binding to Patched de-represses Smoothened. Reason: Ligand-dependent activation of the pathway is the defining action of Shh; in zebrafish, ectopic shha activates ptc1 and Hh target genes wherever it is expressed. Core process, paired with patched binding in core_functions. Supporting Evidence: PMID:12606279 Consistent with a direct role for Hh signaling in pituitary induction and patterning, overexpression of Shh results in expanded adenohypophyseal expression of lim3, expansion of nk2.2 into the posterior adenohypophysis, and an increase in Prolactin- and Somatolactin-secreting cells. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning prediction of 'animal organ development' from sequence/family features. Reason: Biologically true for shha but so general that it conveys nothing beyond the many specific developmental annotations already present; flagged as over-annotation. |
| GO:0048557 embryonic digestive tract morphogenesis | IMP PMID:19123126 Hedgehog signalling is required for cloacal development in t... | KEEP AS NON CORE | Summary: Hh signalling from the endoderm is absolutely required for cloaca formation (34-74 hpf). Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:19123126 we demonstrate that Hh signalling is absolutely required for the formation of the zebrafish cloaca |
| GO:0048618 post-embryonic foregut morphogenesis | IMP PMID:12618131 Unique and conserved aspects of gut development in zebrafish... | KEEP AS NON CORE | Summary: The syu mutation causes oesophageal defects paralleling mouse Shh knockouts and reciprocally affects liver and pancreas. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12618131 a loss-of-function mutation that perturbs sonic hedgehog causes defects in the development of the esophagus that parallel those associated with targeted disruption of this gene in mammals |
| GO:0048663 neuron fate commitment | IGI PMID:15539490 Spatial and temporal regulation of ventral spinal cord precu... | KEEP AS NON CORE | Summary: olig2+ precursors give rise to motoneurons and interneurons under spatial and temporal control of Hh signalling. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 Graded Hedgehog (Hh) signaling patterns the spinal cord dorsoventral axis by inducing and positioning distinct precursor domains, each of which gives rise to a different type of neuron. PMID:15539490 we provide evidence that these biases emerge from Hh acting over time to set, maintain, subdivide and enlarge the olig2+ precursor domain and subsequently specify oligodendrocyte development |
| GO:0048702 embryonic neurocranium morphogenesis | IGI PMID:16049113 Hedgehog signaling is required for cranial neural crest morp... | KEEP AS NON CORE | Summary: shh is required for midline movements of trabecular/ethmoid neural crest progenitors and their chondrogenesis. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16049113 By analyzing zebrafish mutants that disrupt sonic hedgehog (shh) expression, we demonstrate that shh is required to specify the movements of progenitors of these elements at the midline, and to induce them to form cartilage. |
| GO:0048702 embryonic neurocranium morphogenesis | IMP PMID:16049113 Hedgehog signaling is required for cranial neural crest morp... | KEEP AS NON CORE | Summary: shh is required for midline movements of trabecular/ethmoid neural crest progenitors and their chondrogenesis. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16049113 By analyzing zebrafish mutants that disrupt sonic hedgehog (shh) expression, we demonstrate that shh is required to specify the movements of progenitors of these elements at the midline, and to induce them to form cartilage. |
| GO:0048703 embryonic viscerocranium morphogenesis | IGI PMID:16481351 Early Hedgehog signaling from neural to oral epithelium orga... | KEEP AS NON CORE | Summary: shha/shhb from the ventral brain primordium specify the stomodeum, which then supports condensation of upper-jaw and anterior neurocranial crest. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16481351 we propose that Hh signaling from the brain primordium is required for proper specification of the stomodeum and the stomodeum, in turn, promotes condensation of a subset of neural crest cells that will form the anterior neurocranial and upper jaw cartilage |
| GO:0048703 embryonic viscerocranium morphogenesis | IMP PMID:16580747 Impairment of lower jaw growth in developing zebrafish expos... | KEEP AS NON CORE | Summary: syu mutants and cyclopamine reproduce the lower-jaw growth impairment caused by TCDD, which down-regulates shha/shhb. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:16580747 Loss of Hh signaling in mutants (sonic you) and larvae treated with a Hh inhibitor (cyclopamine), resulted in similar effects as those caused by TCDD. |
| GO:0048709 oligodendrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT node PTN002484206, seeded by the zebrafish shha experimental annotation itself (target in its own WITH/FROM, as expected). Reason: Shh maintains olig2 expression and drives OPC generation from pMN precursors. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:15539490 we provide evidence that these biases emerge from Hh acting over time to set, maintain, subdivide and enlarge the olig2+ precursor domain and subsequently specify oligodendrocyte development PMID:23345245 Ihhb is required for the cell cycle inhibition of the spinal precursors involved in OPC specification, while Shh has a stimulatory effect on the cell cycle progression and maintenance of olig2 expression. |
| GO:0048709 oligodendrocyte differentiation | IMP PMID:23345245 Indian hedgehog B function is required for the specification... | KEEP AS NON CORE | Summary: Shh stimulates cell-cycle progression and maintains olig2 in pMN precursors but cannot substitute for Ihhb in OPC specification. Reason: The shha-specific evidence is heat-shock overexpression (Tg(uas:shha)); the paper's main point is that Ihhb, not Shh, times OPC specification. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:23345245 Ihhb is required for the cell cycle inhibition of the spinal precursors involved in OPC specification, while Shh has a stimulatory effect on the cell cycle progression and maintenance of olig2 expression. |
| GO:0048741 skeletal muscle fiber development | IDA PMID:17699609 Pbx homeodomain proteins direct Myod activity to promote fas... | KEEP AS NON CORE | Summary: Shh requires Myod to induce fast- and slow-muscle markers and Pbx to induce fast-muscle markers. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17699609 Furthermore, we show that Sonic hedgehog requires Myod in order to induce both fast- and slow-muscle markers but requires Pbx only to induce fast-muscle markers. |
| GO:0048741 skeletal muscle fiber development | IGI PMID:17699609 Pbx homeodomain proteins direct Myod activity to promote fas... | KEEP AS NON CORE | Summary: Shh requires Myod to induce fast- and slow-muscle markers and Pbx to induce fast-muscle markers. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17699609 Furthermore, we show that Sonic hedgehog requires Myod in order to induce both fast- and slow-muscle markers but requires Pbx only to induce fast-muscle markers. |
| GO:0048741 skeletal muscle fiber development | IGI PMID:17699609 Pbx homeodomain proteins direct Myod activity to promote fas... | KEEP AS NON CORE | Summary: Shh requires Myod to induce fast- and slow-muscle markers and Pbx to induce fast-muscle markers. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:17699609 Furthermore, we show that Sonic hedgehog requires Myod in order to induce both fast- and slow-muscle markers but requires Pbx only to induce fast-muscle markers. |
| GO:0048793 pronephros development | IMP PMID:10885753 The zebrafish floating head mutant demonstrates podocytes pl... | KEEP AS NON CORE | Summary: In syu (and flh, yot) mutants glomeruli differentiate at ectopic lateral positions; podocyte differentiation is unaffected. Reason: The effect is indirect: loss of midline/dorsal aorta signals mispositions the glomerulus without blocking podocyte differentiation. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:10885753 In flh, syu, and yot mutants, glomeruli differentiate at ectopic lateral positions within the embryo and contain morphologically identifiable podocyte and endothelial cell types. PMID:10885753 Our results suggest that midline signals are required for proper glomerular morphogenesis but not for the differentiation of podocytes. |
| GO:0048795 swim bladder morphogenesis | IMP PMID:19422819 Development of zebrafish swimbladder: The requirement of Hed... | KEEP AS NON CORE | Summary: shha (with ihha) is expressed in swimbladder epithelium; Hh pathway mutants fail to specify and organise the three swimbladder layers. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:19422819 By analyzing several mutants affecting Hh signaling and Ihha morphants, we demonstrated an essential role of Hh signaling in swimbladder development. |
| GO:0048839 inner ear development | IGI PMID:12588855 Hedgehog signalling is required for correct anteroposterior ... | KEEP AS NON CORE | Summary: shha and shhb redundantly pattern the otic vesicle along the A/P axis. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:12588855 By using double mutants and antisense morpholino analysis, we also show that both Sonic hedgehog and Tiggy-winkle hedgehog are involved in anteroposterior patterning of the zebrafish otic vesicle. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning prediction of 'regulation of developmental process' from sequence/family features. Reason: Biologically true for shha but so general that it conveys nothing beyond the many specific developmental annotations already present; flagged as over-annotation. |
| GO:0055002 striated muscle cell development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of 'striated muscle cell development' from sequence/family features. Reason: Consistent with the experimental annotations for shha; retained as a non-core generalisation of the specific developmental roles. |
| GO:0055002 striated muscle cell development | IMP PMID:11428131 Gli2 mediation of hedgehog signals in slow muscle induction ... | KEEP AS NON CORE | Summary: syu mutants form only a few slow muscle cells; Gli2 mediates Shh, Twhh and Ehh in slow-muscle induction. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:11428131 In yot mutant embryos, development of slow muscles was completely blocked, whereas in syu mutant embryos, a small number of slow muscle cells could still form, suggesting that other Hhs were also involved in slow muscle induction. |
| GO:0060956 endocardial cell differentiation | IGI PMID:22119054 Hedgehog signaling is required for differentiation of endoca... | KEEP AS NON CORE | Summary: Combined shh/twhh knockdown (or smo loss) abolishes endocardial marker expression; notochord Hh specifies endocardial progenitors. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:22119054 Simultaneous knockdown of the two zebrafish sonic hedgehog homologs, shh and twhh or Hh co-receptor smoothened (smo) resulted in similar defects in endocardial morphogenesis. |
| GO:0061035 regulation of cartilage development | IGI PMID:22185793 Analysis of sphingosine-1-phosphate signaling mutants reveal... | KEEP AS NON CORE | Summary: Transgenic Shha misexpression restores ectodermal fgf8a and partially rescues jaw cartilage growth in endoderm-less sox32 mutants. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:22185793 transgenic misexpression of Shha restores fgf8a expression and partially rescues the growth and differentiation of jaw skeletal precursors |
| GO:0070444 oligodendrocyte progenitor proliferation | IMP PMID:23345245 Indian hedgehog B function is required for the specification... | KEEP AS NON CORE | Summary: Heat-shock shha overexpression dramatically increases BrdU+ proliferating olig2+ precursors in the spinal cord. Reason: Gain-of-function evidence for a pro-proliferative effect on oligodendrocyte lineage precursors. shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:23345245 This suggests that in contrast to Ihhb, Shh has a stimulatory effect on cell cycle progression during oligodendrogenesis. |
| GO:0140853 cholesterol-protein transferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Intramolecular cholesterol-protein transferase activity of the Hint C-terminal domain, transferred from mouse Shh (UniProt catalytic activity, RHEA:59504). Reason: The Hedgehog C-terminal domain is the defining example of this activity; zebrafish Shh is shown to autoprocess in vivo and the catalytic residues (Cys198 thioester, Asp303/His329 equivalents annotated by UniProt as SITE) are conserved. Core molecular function of the precursor. Supporting Evidence: PMID:8824192 Here it is reported that cholesterol is the lipophilic moiety covalently attached to the amino-terminal signaling domain during autoprocessing and that the carboxyl-terminal domain acts as an intramolecular cholesterol transferase. PMID:7583153 Both twhh and shh proteins undergo autoproteolytic processing in vivo; a fragment corresponding to the amino-terminal cleavage product was sufficient to carry out all signaling activities associated with twhh in eye and brain development. |
| GO:1905178 regulation of cardiac muscle tissue regeneration | IMP PMID:28513431 Dissection of zebrafish shha function using site-specific ta... | KEEP AS NON CORE | Summary: Epicardial shha knockout reduces subepicardial cardiomyocyte proliferation after cardiac injury. Reason: shha is a pleiotropic morphogen: its single molecular activity (the lipidated ShhN ligand binding Patched and activating Smoothened signalling) is deployed in many tissues. This annotation records one such developmental deployment, so it is retained but flagged non-core; the core functions are the ligand activity and precursor autoprocessing. Supporting Evidence: PMID:28513431 These findings support the role of epicardial Shha in transmitting direct, short-range signals that promote the proliferation of adjacent cardiomyocytes during zebrafish heart regeneration. |
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Download this section (compressed HTML)Q: Which shha developmental phenotypes are shared with shhb, and which are unique to shha? Systematic single and double mutant (rather than morpholino) comparison would let ZFIN separate redundant from shha-specific roles.
Q: Does zebrafish Shha act as a long-range morphogen anywhere (e.g. neural tube, fin bud), or is signalling predominantly short-range/juxtacrine as the retina and epicardium studies suggest? This bears on whether GO:0016015 morphogen activity should be added, which was deliberately not proposed here.
Q: Is the Rohon-Beard axon phenotype of syu mutants entirely explained by loss of muscle contraction, or does Shha also act as a direct guidance cue for motor or retinal ganglion cell axons in zebrafish as it does at the mammalian optic chiasm?
Q: Does the shha heterozygote cone phenotype reflect a continuing adult requirement for Shh signalling in cone survival, or a developmental sensitisation?
Experiment: Generate clean shha; shhb double mutants (CRISPR) and score floor plate, otic, diencephalic, craniofacial and endocardial phenotypes against each single mutant to assign redundancy explicitly.
Experiment: Use the Cre-invertible shha allele with tissue-specific drivers (notochord, floor plate, endoderm, ZLI, fin mesenchyme) to map which source of Shha is responsible for each annotated developmental process.
Experiment: Biochemically confirm autoprocessing and cholesterol transfer for the zebrafish protein (Hint-domain C198A/D303A mutants expressed in embryos), so the ISS-based catalytic annotations gain direct zebrafish evidence.
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