Zebrafish Hes6, also called Her13.2, is a basic helix-loop-helix/Orange protein in the presomitic-mesoderm segmentation clock. It forms dimers with other Hairy-related factors and contributes to a DNA-binding transcriptional repressor with Her7. The availability of different dimers helps control transcriptional oscillations and somite formation. Hes6 homodimers do not show the strong DNA binding of Her7:Hes6 heterodimers in the tested promoter assays.
Existing Annotations Review
GO Term
Evidence
Action
Reason
GO:0000122 negative regulation of transcription by RNA polymerase II
IBA GO_REF:0000033
ACCEPT
Summary: Negative regulation of RNA polymerase II transcription is central to the Hes6-containing segmentation-clock circuit. Target-specific reporter and DNA-binding experiments support the IBA independently of general Hairy-family naming.
Her13.2 augments autorepression of her1 in association with Her1 protein.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IBA GO_REF:0000033
ACCEPT
Summary: Her7:Hes6 heterodimers bind specific sites in cyclic-gene promoters directly. This supports the term in a heteromeric context; it does not assert that isolated Hes6 or its homodimer binds those sites. A contributes_to qualifier best expresses the subunit contribution.
Summary: Hes6 contributes to a DNA-binding repressor with Her7, coupling promoter recognition to cyclic transcription. The IBA function is supported in that complex context; an autonomous Hes6 homodimeric transcription factor is not established.
IGI PMID:16545363 her1 and her13.2 are jointly required for somitic border spe...
ACCEPT
Summary: The cited study explicitly reports loss of somitic borders after combined her1/her13.2 inactivation, directly supporting the core segmentation role.
IGI PMID:20637625 Segment number and axial identity in a segmentation clock pe...
ACCEPT
Summary: The clock-period mutant study and independently documented hes6 identity support a genetic contribution to somite timing and number. Full-text follow-up explicitly identifies this mutant as hes6.
IMP PMID:16545363 her1 and her13.2 are jointly required for somitic border spe...
ACCEPT
Summary: The study directly tests her13.2 loss of function, including the enhanced phenotype in combination with her1. The abstract establishes the target and somitic phenotype; no unsupported exact assay detail is inferred.
IMP PMID:20637625 Segment number and axial identity in a segmentation clock pe...
ACCEPT
Summary: This separate GOA perturbation row represents the same experimentally grounded core somitogenesis function. The biological conclusion is supported without collapsing distinct curator-recorded reagents or genotypes.
IMP PMID:29624170 Segmentation of the zebrafish axial skeleton relies on notoc...
ACCEPT
Summary: The full paper generates a new hes6 TALEN allele and tests clock-mutant combinations, including her1;hes6 embryos with disordered myotome boundaries. Its conclusion that centra can segment independently of the clock does not contradict Hes6 function in somite formation.
Summary: Generic DNA binding is supported in the Her7:Hes6 complex, but promoter-sequence-specific DNA binding is more informative. The target contributes as a heterodimeric subunit rather than an independently DNA-binding homodimer.
IPI PMID:22911291 Topology and dynamics of the zebrafish segmentation clock co...
MODIFY
Summary: The Her1 interaction is a defined bHLH heterodimerization event in the clock network, better represented by protein heterodimerization than generic protein binding. Her1:Hes6 does not share the strong DNA binding of Her7:Hes6.
IPI PMID:22911291 Topology and dynamics of the zebrafish segmentation clock co...
KEEP AS NON CORE
Summary: The donor is Myod1, and the full paper actually tests this interaction as an example of promiscuous bHLH association. Retain the measured binding as non-core; it does not establish a physiological myogenic function for Hes6.
even the bHLH containing factor MyoD, but not the negative control non-bHLH protein PPARΞ³, was co-purified by Her1, Her7, and Hes6 to a similar extent
IPI PMID:22911291 Topology and dynamics of the zebrafish segmentation clock co...
MODIFY
Summary: The Her7 interaction forms the directly characterized DNA-binding Her7:Hes6 heterodimer. Protein heterodimerization describes this molecular event more precisely than generic protein binding.
Summary: The conserved nuclear-location inference is consistent with target-specific promoter binding and transcriptional repression. The functional evidence supports nuclear action without establishing exclusive localization.
Summary: Nuclear localization is a reasonable inference for the directly characterized transcriptional repressor component. It is supported by the biological mechanism, not by the UniRule assertion alone.
Summary: The broad transcription association is valid, but Hes6 regulates transcription negatively rather than catalyzing RNA synthesis. Use the specific negative-regulation term.
only Her1 homodimers and Her7:Hes6 heterodimers have strong DNA binding activity and target similar DNA sites.
GO:0006355 regulation of DNA-templated transcription
IEA GO_REF:0000120
MODIFY
Summary: The transcriptional role is directly supported and can be specified as negative regulation of RNA polymerase II transcription in the segmentation clock.
Summary: Hes6 affects segment number and organization along the anterior/posterior axis. Retain this broad developmental association as non-core, while the period-mutant experiments argue against interpreting it as instructive determination of Hox-associated axial identity.
IC PMID:15905406 Zebrafish hairy/enhancer of split protein links FGF signalin...
ACCEPT
Summary: The inferred repressor complex is supported by the original interaction/repression assays and the directly characterized Her7:Hes6 DNA-binding heterodimer. Different possible dimers need not have equivalent repressor activity.
IPI PMID:22911291 Topology and dynamics of the zebrafish segmentation clock co...
MODIFY
Summary: Direct assays show Hes6 self-association, so protein homodimerization is more informative than identical protein binding. The resulting homodimer lacks the strong promoter DNA binding of Her7:Hes6.
only Her1 homodimers and Her7:Hes6 heterodimers have strong DNA binding activity and target similar DNA sites.
GO:0045892 negative regulation of DNA-templated transcription
IDA PMID:15905406 Zebrafish hairy/enhancer of split protein links FGF signalin...
ACCEPT
Summary: The reporter experiments directly establish enhanced her1 autorepression in association with Her13.2/Hes6, supporting a core negative transcriptional role.
Her13.2 augments autorepression of her1 in association with Her1 protein.
GO:0045892 negative regulation of DNA-templated transcription
IGI PMID:15905406 Zebrafish hairy/enhancer of split protein links FGF signalin...
ACCEPT
Summary: The genetic and expression experiments place Hes6 upstream of periodic repression of her1 and her7, consistent with the interaction-based repression mechanism.
IPI PMID:15905406 Zebrafish hairy/enhancer of split protein links FGF signalin...
ACCEPT
Summary: Her13.2/Hes6 association with Her1 is directly tested, and broader biophysical experiments establish heterodimer formation with clock components.
Summary: Both homo- and heterodimer formation are experimentally demonstrated, so the broad dimerization term is accurate. The distinct specific dimer classes are also represented in this review.
Summary: The IBA is an ancestral Hairy-family neurogenesis inference. The inspected target studies establish mesodermal clock function but neither test nor refute a neural role of zebrafish Hes6. Mammalian Hes6 biology or the zebrafish her6 name cannot resolve the target-specific scope without further phylogenetic or experimental evidence.
Q: Does zebrafish Hes6 have a neural role distinct from its experimentally established presomitic segmentation-clock function?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
DNA binding, transcriptional regulation and dimerization are experimentally grounded in zebrafish Hes6. Their broad labels omit partner dependence and the specific negative transcriptional role.
Review rationale: Direct assays establish sequence-specific promoter binding by Her7:Hes6, already covered by the more specific GOA term. Generic DNA binding is valid for the complex contribution but must not be interpreted as autonomous Hes6 homodimer binding.
Supporting Evidence:
PMID:22911291: "only Her1 homodimers and Her7:Hes6 heterodimers have strong DNA binding activity and target similar DNA sites."
GO:0006355 regulation of DNA-templated transcriptionGO_BP
LSP β Less precise than existing annotation Review score: 2/2
Review rationale: Hes6-dependent negative transcriptional regulation is established by reporter, genetic and biochemical experiments and already represented more specifically in GOA.
Supporting Evidence:
PMID:15905406: "Her13.2 augments autorepression of her1 in association with Her1 protein."
PMID:15905406: "her13.2 is required for periodic repression of the Notch-regulated genes her1 and her7, and for proper somite segmentation."
Review rationale: Both homo- and heterodimerization are directly demonstrated and the same broad term is already present in GOA. Different dimer combinations have different DNA-binding capabilities.
Supporting Evidence:
PMID:22911291: "all of the possible dimers between Her1, Her7 and Hes6 form"
PMID:22911291: "only Her1 homodimers and Her7:Hes6 heterodimers have strong DNA binding activity and target similar DNA sites."