ARX is a paired homeobox transcription factor that binds cis-regulatory DNA and activates or represses gene expression according to target and cellular context. It acts in the nucleus and participates in neuronal development, pancreatic alpha-cell specification and selected intestinal endocrine lineages. ARX can cooperate with the histone demethylase PHF8 in activating KDM5C. Pathogenic ARX variants cause a spectrum of X-linked neurodevelopmental disorders, including developmental and epileptic encephalopathy, Partington syndrome and lissencephaly with abnormal genitalia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:22194193 ARX homeodomain mutations abolish DNA binding and lead to a ... | ACCEPT | Summary: Human ARX represses LMO1/SHOX2 transcription. Reason: The source reporter, endogenous expression and DNA-binding experiments establish transcriptional repression by wild-type human ARX. Human full-length constructs and HEK293T Methods were read externally; the normal record remains abstract-only. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived repression inference agrees with direct human ARX assays. Reason: The O35085/Ensembl transfer is independently corroborated by human wild-type ARX repression of LMO1 and SHOX2. The original electronic source remains distinct from that human experiment. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0000785 chromatin | IDA PMID:22194193 ARX homeodomain mutations abolish DNA binding and lead to a ... | ACCEPT | Summary: ARX occupies endogenous regulatory chromatin. Reason: Full-length Myc-ARX ChIP enriches LMO1 and SHOX2 regulatory sites in the original human-construct experiment. This supports functional chromatin association, without implying constitutive binding throughout the genome. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: The transcription-factor classification places ARX on chromatin. Reason: The TFClass inference is consistent with direct ARX chromatin occupancy in the human-target ChIP experiments. TFClass alone is not used to infer a particular regulatory locus. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ARX recognizes sequence-specific transcriptional regulatory DNA. Reason: The PAINT assertion at PTN004692309 agrees with ARX EMSA competition/supershift and promoter ChIP. Complete ancestral topology was not inspected; no loss/divergence evidence argues against this inherited activity, and ARX as a descendant source is not circular. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:22194193 ARX homeodomain mutations abolish DNA binding and lead to a ... | ACCEPT | Summary: ARX recognizes LMO1/SHOX2 regulatory sequences. Reason: The original EMSA and ChIP experiments link ARX sequence recognition to repression of these targets. Actual human constructs and controls were read; the cache availability flag remains abstract-only. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:31691806 Histone demethylase KDM5C is a SAHA-sensitive central hub at... | ACCEPT | Summary: ARX occupies KDM5C cis-regulatory regions. Reason: The source identifies ARX-responsive KDM5C promoter regions and measures occupancy by wild-type and pathogenic ARX constructs. The read promoter experiments support cis-regulatory DNA binding; downstream chromatin chemistry belongs to the demethylases. Supporting Evidence: |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived cis-regulatory binding inference matches human ARX experiments. Reason: Human ARX binding to LMO1/SHOX2 and KDM5C regulatory DNA independently corroborates this ortholog transfer, while retaining the original O35085/Ensembl provenance. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ARX is a sequence-specific RNA polymerase II transcription factor. Reason: Direct DNA recognition coupled to repression and activation supports this PAINT-derived activity. PTN004692309 is preserved as the ancestral source; the complete node reconstruction was not read and no donor-count or self-source objection is made. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:16301625 Identification of the immunodominant HY H2-D(k) epitope and ... | ACCEPT | Summary: ARX transcription-factor activity is independently established; this cited experiment is unresolved. Reason: The broad function is clearly supported by the independent human ARX binding/repression and KDM5C activation studies. PMID16301625 is retained unchanged: its available abstract describes HY/Smcy antigen presentation, and the source-local ARX assay has not been verified. Accept the biological assertion while deferring its original experimental provenance to the curator; do not infer misattribution from the abstract. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000120 | ACCEPT | Summary: The combined homeobox and ortholog inference matches ARX transcriptional activity. Reason: Human ARX recognizes regulatory DNA and changes transcription, corroborating the combined O35085/Ensembl/IPR017970 inference. Domain presence alone is not being used to assign activation versus repression. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: ARX fits the DNA-binding transcription-factor class. Reason: The TFClass assertion agrees with experimental DNA binding and locus-dependent transcriptional effects; it does not imply that every ARX target responds in the same direction. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:22194193 ARX homeodomain mutations abolish DNA binding and lead to a ... | ACCEPT | Summary: DNA-bound ARX represses selected target genes. Reason: The same paper connects wild-type ARX sequence recognition with reporter and endogenous LMO1/SHOX2 repression. Loss of binding in several homeodomain mutants accompanies reduced repression. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: The transferred repressor activity is directly corroborated in human ARX. Reason: The mouse-derived annotation is consistent with the human wild-type DNA-binding/repression experiments, not merely with ARX domain architecture. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:31691806 Histone demethylase KDM5C is a SAHA-sensitive central hub at... | ACCEPT | Summary: ARX activates KDM5C transcription in a promoter-dependent assay. Reason: KDM5C reporter activation and ARX promoter occupancy support the activator activity. Cooperation with PHF8 is context-dependent and does not make ARX itself a histone demethylase. Supporting Evidence: PMID:31691806 ARX plus PHF8 caused a cumulative luciferase increase mediating a strong response (205%; |
| GO:0003310 pancreatic A cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ARX supports pancreatic alpha-cell specification. Reason: The mouse O35085 transfer is corroborated by independent human ARX-deficient hESC endocrine cultures and XLAG pancreatic tissue showing deficient glucagon-cell development. The human re-expression protocol increased C-peptide release without restoring glucagon release in the tested comparison, so a universal alpha-cell rescue is not claimed. Supporting Evidence: PMID:26633894 XLAG pancreatic tissue lacked glucagon and PP-positive cells, but contained insulin, somatostatin, and ghrelin-positive cells |
| GO:0003310 pancreatic A cell differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: The curated ortholog transfer captures pancreatic alpha-cell differentiation. Reason: The ISS source remains mouse O35085. Independent human stem-cell and patient-tissue observations support the same broad developmental role without rewriting that original evidence or assigning a direct target-gene mechanism. Supporting Evidence: PMID:26633894 XLAG pancreatic tissue lacked glucagon and PP-positive cells, but contained insulin, somatostatin, and ghrelin-positive cells |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: The ARX homeodomain binds DNA. Reason: The IPR001356 inference is supported directly by ARX EMSA and chromatin occupancy. More specific sequence-specific and transcription-factor assertions already occur in this audit; the original broad source term is retained. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: ARX associates with target regulatory chromatin. Reason: The O35085/Ensembl chromatin-binding transfer agrees with human ARX ChIP at LMO1/SHOX2 and KDM5C. It does not imply that ARX recognizes a histone modification directly. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | UNDECIDED | Summary: The ARX–ACTN1 screen pair needs source-local experimental closure. Reason: The source uses full/partial human baits, a brain cDNA library and secondary interaction tests. Its exact ARX–ACTN1 construct/pair and validation entry remain unread. The named GOA partner and UniProt interaction list are preserved, but do not resolve the specific assay route. No false interaction or cytoskeletal function is inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21653829 Protein interactome reveals converging molecular pathways am... | UNDECIDED | Summary: The ARX–PICK1 screen pair needs source-local experimental closure. Reason: The main screen and general validation Methods were read, but the supplementary ARX–PICK1 pair/construct entry was not recovered. The UniProt-listed pair is corroborative; it does not establish whether this particular source used a fragment or mammalian validation. No adaptor, kinase or other narrower ARX activity is manufactured from the partner name. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:34356104 Analysis of a Set of KDM5C Regulatory Genes Mutated in Neuro... | MODIFY | Summary: ARX associates with the histone demethylase PHF8. Reason: The same source demonstrates reciprocal endogenous ARX–PHF8 co-immunoprecipitation in SH-SY5Y cells and tagged-protein confirmation. PHF8 is a catalytic enzyme, so enzyme binding specifies the partner class without attributing demethylation to ARX. The evidence supports cellular association, not a purified binary interface. Proposed replacements: enzyme binding Supporting Evidence: PMID:34356104 endogenous ARX was immunoprecipitated by the anti-PHF8 antibody and vice versa |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: ARX acts as a nuclear transcription factor. Reason: The inherited nuclear assertion at PTN004692309 is corroborated by human ARX nuclear localization and chromatin-dependent transcription. The actual ancestral topology remains uninspected; no contrary target-specific evidence is apparent. Supporting Evidence: file:human/ARX/ARX-notes.md Wild-type protein is predominantly nuclear. |
| GO:0005634 nucleus | IDA PMID:22194193 ARX homeodomain mutations abolish DNA binding and lead to a ... | ACCEPT | Summary: Wild-type ARX is predominantly nuclear. Reason: The original cell-localization Results and figure captions show mainly nuclear wild-type human ARX. Mutant aggregation and mislocalization are not used to redefine the normal protein. Supporting Evidence: file:human/ARX/ARX-notes.md Wild-type protein is predominantly nuclear. |
| GO:0005634 nucleus | IDA PMID:31691806 Histone demethylase KDM5C is a SAHA-sensitive central hub at... | ACCEPT | Summary: ARX operates at a nuclear KDM5C promoter. Reason: The source combines nuclear localization/occupancy assays with promoter activity. Its nuclear role is also independently supported by the earlier human ARX localization study. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: The electronic nuclear-location mapping is biologically supported. Reason: SL-0191 agrees with observed nuclear ARX and its DNA-bound transcriptional activity; no default localization is being inferred merely from absence of a signal peptide. Supporting Evidence: file:human/ARX/ARX-notes.md Wild-type protein is predominantly nuclear. |
| GO:0005694 chromosome | IEA GO_REF:0000044 | ACCEPT | Summary: ARX associates with chromosomal regulatory DNA. Reason: The preserved SL-0468 chromosome mapping is consistent with endogenous regulatory-chromatin ChIP and the source UniProt location evidence. This does not assert stable mitotic chromosome coating. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: ARX regulates DNA-templated transcription. Reason: The homeobox-domain inference agrees with experimentally demonstrated repression and activation. The broad term is retained in the audit, while the core will identify the specific DNA-binding transcription-factor activity. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited transcriptional regulation is supported by human ARX assays. Reason: The PTN004692309 assertion agrees with promoter occupancy and bidirectional, locus-dependent transcriptional effects. The donor list is not treated as a substitute for phylogeny or as a weakness. Supporting Evidence: PMID:22194193 wild-type ARX repressed endogenous expression of known ARX targets, LMO1 and SHOX2 |
| GO:0030182 neuron differentiation | IEA GO_REF:0000117 | ACCEPT | Summary: ARX participates in neuronal differentiation programs. Reason: Mutant mouse forebrain and ES-derived neuronal models support ARX-dependent interneuron development and downstream KDM5C regulation, with human disease variants corroborating relevance. The ARBA inference is accepted at this broad developmental level; no specific human lineage assay is invented. Supporting Evidence: PMID:12379852 These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex |
| GO:0035883 enteroendocrine cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ARX contributes to enteroendocrine lineage specification. Reason: The mouse transfer is independently corroborated by human ARX knockdown in intestinal organoids, where selected hormone-lineage markers decline while general intestinal and pan-endocrine markers remain. Effects differ among subtypes, so this broad function does not automatically validate every specific G/I/L/N/D source row. Supporting Evidence: PMID:22387004 In mice, removal of Arx from the developing endoderm results in a decrease of enteroendocrine cell types including gastrin-, glucagon/GLP-1-, CCK-, secretin-producing cell populations and an increase of somatostatin-expressing cells. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:31691806 Histone demethylase KDM5C is a SAHA-sensitive central hub at... | ACCEPT | Summary: ARX positively regulates KDM5C transcription. Reason: The source promoter reporter and occupancy experiments demonstrate activation by ARX in the tested cellular context. Activation and repression at other loci are compatible properties of this transcription factor. Supporting Evidence: PMID:31691806 ARX plus PHF8 caused a cumulative luciferase increase mediating a strong response (205%; |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived positive-transcription inference agrees with human promoter assays. Reason: Independent ARX-mediated KDM5C activation supports this transfer. It does not imply that all ARX targets are activated or that ARX supplies PHF8/KDM5C catalytic activity. Supporting Evidence: PMID:31691806 ARX plus PHF8 caused a cumulative luciferase increase mediating a strong response (205%; |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IGI PMID:31691806 Histone demethylase KDM5C is a SAHA-sensitive central hub at... | ACCEPT | Summary: ARX and PHF8 cooperate in KDM5C promoter activation. Reason: The source tests ARX and PHF8 together and reports enhanced promoter output. Retain the genetic-interaction provenance; direct binary contact was not demonstrated in this 2019 experiment, and the 2021 co-IP is separate corroboration. Supporting Evidence: PMID:31691806 ARX plus PHF8 caused a cumulative luciferase increase mediating a strong response (205%; |
| GO:0048666 neuron development | IBA GO_REF:0000033 | ACCEPT | Summary: ARX has an inherited role in neuron development. Reason: The PTN001216073 IBA agrees with mouse interneuron development defects and the ARX–KDM5C neuronal transcriptional axis. Complete PAINT topology was not read, and no target loss/divergence argument supports rejecting the ancestral judgment. Human disease association is distinguished from direct mouse perturbation. Supporting Evidence: PMID:12379852 These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex |
| GO:0048666 neuron development | IEA GO_REF:0000107 | ACCEPT | Summary: The rat-derived neuron-development transfer fits conserved ARX biology. Reason: The A6YP92/Ensembl inference is corroborated independently by mouse developmental experiments, conserved neuronal transcriptional effects and human ARX disease. No rat-specific assay or donor topology was newly reconstructed. Supporting Evidence: PMID:12379852 These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: ARX binds double-stranded DNA with sequence specificity. Reason: The exact ARX construct/motif entry in the methylation-sensitive SELEX supplement remains unread. The broad assertion is nevertheless directly corroborated by ARX-specific EMSA competition and ChIP. Preserve the original IDA source and defer its detailed assay provenance; do not infer an ARX methyl-CpG preference. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic sequence-specific DNA-binding inference is supported. Reason: Direct human ARX binding to regulatory motifs validates the broad ARBA assertion. No methylation preference or additional biochemical specificity is inferred. Supporting Evidence: PMID:22194193 Electrophoretic mobility shift assay results were validated using chromatin immunoprecipitation |
| GO:7770021 intestinal type G enteroendocrine cell differentiation | IDA PMID:37883554 Unbiased transcription factor CRISPR screen identifies ZNF80... | UNDECIDED | Summary: The cited human G-cell differentiation endpoint remains unresolved. Reason: The actual 2023 target Results show ARX overexpression and tested-locus ChIP in a ZNF800-null organoid context, not a verified positive human gastrin-cell endpoint. The discussion cites earlier mouse work, while the supplementary ARX assays remain unread. This does not refute ARX function in normal G-cell specification. Supporting Evidence: |
| GO:7770021 intestinal type G enteroendocrine cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse-derived evidence supports an ARX role in G-cell specification. Reason: The current O35085 donor record and original conditional-mouse study support gastrin-lineage differentiation. Conserved human endocrine roles support the existing ortholog inference, but no positive human G-cell experiment is attributed to the 2023 source. Supporting Evidence: PMID:22387004 In mice, removal of Arx from the developing endoderm results in a decrease of enteroendocrine cell types including gastrin-, glucagon/GLP-1-, CCK-, secretin-producing cell populations and an increase of somatostatin-expressing cells. |
| GO:7770022 intestinal type I enteroendocrine cell differentiation | IDA PMID:37883554 Unbiased transcription factor CRISPR screen identifies ZNF80... | ACCEPT | Summary: Independent human evidence supports ARX participation in I-cell differentiation. Reason: Accept the biological function on independent human ARX knockdown and conditional-mouse lineage evidence, while deferring the original 2023 assay provenance to its curator. In PMID:22387004, stable ARX shRNA in WA09-derived proximal intestinal organoids reduced CCK expression at day 68 while general epithelial and pan-endocrine markers were maintained. This is a developmental marker endpoint, not a counted mature I-cell census. The specific positive ARX experiment behind PMID:37883554 remains unverified; its conditional ZNF800-null overexpression results do not negate the independently supported role. Supporting Evidence: PMID:22387004 ARX knockdown did cause a 60–80% reduction in CCK, Secretin, and Preproglucagon mRNA levels |
| GO:7770022 intestinal type I enteroendocrine cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ARX supports differentiation of the CCK-producing intestinal lineage. Reason: The O35085 transfer is supported by conditional-mouse lineage results and independent human organoid ARX knockdown that reduces CCK while maintaining general epithelial and pan-endocrine markers. The human result is a marker endpoint, not a counted mature-cell census. Supporting Evidence: PMID:22387004 ARX knockdown did cause a 60–80% reduction in CCK, Secretin, and Preproglucagon mRNA levels |
| GO:7770023 intestinal type L enteroendocrine cell differentiation | IDA PMID:37883554 Unbiased transcription factor CRISPR screen identifies ZNF80... | ACCEPT | Summary: Independent human and mouse evidence supports ARX participation in L-cell differentiation. Reason: Accept the biological function on independent human ARX knockdown and mouse lineage evidence, while retaining the original source and evidence code. PMID:22387004 reports reduced preproglucagon in developing human proximal intestinal organoids and reduced glucagon/GLP-1 cell populations after mouse Arx loss. These complementary findings support the existing differentiation assertion; the human marker assay does not establish every mature ileal or colonic L-cell feature. The exact 2023 source-local positive assay remains unread and is deferred to the curator, rather than being attributed to the independent 2012 study. Supporting Evidence: PMID:22387004 ARX knockdown did cause a 60–80% reduction in CCK, Secretin, and Preproglucagon mRNA levels |
| GO:7770023 intestinal type L enteroendocrine cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ARX supports the glucagon/GLP-producing intestinal lineage. Reason: The current mouse transfer is consistent with reduced glucagon/GLP-1 cell populations after mouse Arx loss and reduced preproglucagon expression after human ARX knockdown. The human proximal-organoid assay does not establish every mature ileal/colonic L-cell feature. Supporting Evidence: PMID:22387004 ARX knockdown did cause a 60–80% reduction in CCK, Secretin, and Preproglucagon mRNA levels |
| GO:7770024 intestinal type N enteroendocrine cell differentiation | IDA PMID:37883554 Unbiased transcription factor CRISPR screen identifies ZNF80... | UNDECIDED | Summary: The cited human N-cell differentiation experiment is unresolved. Reason: The 2023 paper discusses earlier mouse lineage requirements, but its positive human ARX-specific neurotensin endpoint and supplemental construct/panel context were not verified. The uncertainty is source-specific, not evidence that ARX lacks this function. Supporting Evidence: |
| GO:7770024 intestinal type N enteroendocrine cell differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived N-cell specification inference is plausible and retained. Reason: The current reviewed O35085 record assigns the neurotensin-lineage function to Arx. This conserved developmental transfer is retained with its mouse provenance; no positive human neurotensin perturbation is claimed from the 2023 paper or from the separate human CCK/preproglucagon experiments. Supporting Evidence: file:human/ARX/ARX-notes.md Its Gene Ontology table explicitly lists “intestinal type N enteroendocrine cell differentiation” with UniProtKB as the source and two publications. |
| GO:7770025 intestinal type D enteroendocrine cell differentiation | IDA PMID:37883554 Unbiased transcription factor CRISPR screen identifies ZNF80... | UNDECIDED | Summary: The human D-cell differentiation assertion has unresolved source and context. Reason: The source-local supplementary ARX endpoint was not verified. Earlier human proximal intestinal ARX knockdown did not increase somatostatin expression, whereas mouse loss increased somatostatin populations. These context-dependent observations do not demonstrate universal absence, but they do not establish this specific positive human differentiation assertion. |
| GO:7770025 intestinal type D enteroendocrine cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse-to-human D-cell differentiation transfer needs clarification. Reason: The current O35085 summary lists the term, but traced mouse experiments show repression of the somatostatin lineage, and human partial knockdown leaves its marker unchanged. The relation between lineage allocation, negative regulation and participation in D-cell differentiation remains unresolved. Preserve the electronic assertion without translating a context-limited negative into universal loss. Propagation Review Root cause: UNRESOLVED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:O35085 UNRESOLVED Current donor annotation exists, but mouse suppression of the D-cell lineage and unchanged human proximal-organoid somatostatin leave the exact transferred differentiation role unresolved. Supporting Evidence: |
Loading supporting content…
Download this section (compressed HTML)Q: Which original supplemental experiments support the five human ARX enteroendocrine subtype annotations in the 2023 study, and how do they relate to its ZNF800-null overexpression results?
Q: Does ARX participate directly in D-cell differentiation, or does its effect reflect repression and allocation of alternative intestinal endocrine lineages?
Q: What exact construct and assay routes support the original ARX–ACTN1 and ARX–PICK1 screen pairs?
Q: Which endogenous target genes connect ARX DNA binding to each pancreatic, intestinal and neuronal developmental program?
Experiment: Compare ARX loss and wild-type ARX rescue with matched controls in human intestinal organoids with intact ZNF800, sampling proximal and distal protocols separately. Quantify hormone-positive cell proportions and single-cell transcriptional identities alongside CCK, proglucagon, gastrin, neurotensin and somatostatin expression. This would separate altered lineage composition from hormone-expression changes and test the unresolved G-, N- and D-cell contexts without treating the earlier ZNF800-null overexpression result as a general ARX loss-of-function assay.
Hypothesis: ARX controls acquisition of selected enteroendocrine subtype identities rather than only hormone transcript abundance.
Type: Isogenic human intestinal organoid perturbation with rescue and single-cell lineage analysis
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)