myc-a

Summary: Myc-a is a bHLH-LZ Myc family protein; vertebrate Myc binds E-box (CACGTG) cis-regulatory sequences of RNA polymerase II target genes as a heterodimer with Max. The PANTHER node placing this activity spans vertebrate c-Myc orthologs with experimental evidence, and Xenopus myc-a is squarely inside that clade.

Reason: Sequence-specific cis-regulatory DNA binding is a core, phylogenetically conserved activity of c-Myc. All E-box contact residues of the basic region are conserved and the Xenopus xc-myc1 gene behaves like mammalian c-Myc in transformation assays. One stage-specific caveat: in transcriptionally silent cleavage embryos, nuclear c-Myc does not bind DNA with Max. This restricts when the activity operates but does not argue against the IBA.

Summary: RNA polymerase II-specific DNA-binding transcription factor activity, inherited from the vertebrate Myc ancestor. This is the central molecular function of Myc-a, acting via Myc-Max heterodimers on E-boxes.

Reason: Consistent with the human MYC review, where GO:0000981 is the primary core molecular function. No evidence of loss or divergence in Xenopus c-Myc. Xenopus c-Myc is required as a transcriptional regulator upstream of slug and the Myc target Id3 in neural crest-forming ectoderm.

Summary: Same activity as the IBA row, transferred by UniProt curators from human MYC (P01106) on sequence similarity.

Reason: The ISS from human MYC agrees with the phylogenetic inference and the conserved bHLH-LZ/Myc box architecture. It is a duplicate of a correct core annotation and duplicates are acceptable.

Summary: Generic DNA-binding transcription factor activity mapped from InterPro Myc/bHLH signatures.

Reason: Correct but less specific parent of GO:0000981, which the gene also carries. Broad IEA mappings that are correct are kept.

Summary: Myc-a acts in the nucleus as a chromatin-associated transcription factor.

Reason: Xenopus c-Myc protein is nuclear in somatic cells. In oocytes a large maternal pool is stored in the cytoplasm and enters nuclei after fertilization. The nucleus is the site where the protein is active.

Summary: Nuclear localization mapped from the UniProt subcellular location annotation.

Reason: Correct; duplicates the IBA. The oocyte cytoplasmic store is a storage form and does not warrant a separate cytoplasm annotation.

Summary: Broad regulation of DNA-templated transcription, mapped from InterPro.

Reason: Correct but general; the more specific GO:0006357 (regulation of transcription by RNA polymerase II) is also present. Kept as a correct broad IEA.

Summary: Regulation of RNA polymerase II transcription, the process directly carried out by the Myc-Max transcription factor.

Reason: Myc regulates Pol II target genes both by activation through E-boxes with Max and by repression through Miz1. Both modes are conserved, and the chick neural crest study shows the Myc/Miz1 repressive mode in vivo. The neutral parent term captures both modes and is the right level of precision for Xenopus, where activation vs repression of specific targets has not been tested.

Summary: Positive regulation of cell population proliferation, a well-established conserved output of vertebrate c-Myc.

Reason: Phylogenetically sound and correct for c-Myc as a family. Myc's growth and proliferation programme is a pleiotropic, context-dependent output rather than the defining role in the Xenopus embryo. The neural crest requirement for Xenopus c-Myc is explicitly independent of proliferation and cell death. In chick premigratory crest, c-Myc also controls self-renewal without changing proliferation.

Summary: Protein dimerization activity via the HLH-leucine zipper, which mediates obligate heterodimerization with Max.

Reason: Consistent with the human MYC review. Heterodimerization with Max is required for E-box binding, and the bHLH-LZ domain is fully conserved in Myc-a. Lemaitre et al. show that Xenopus c-Myc/Max complexes form in vitro and are regulated during early development.

Summary: Member of the Myc-Max heterodimeric transcription factor complex.

Reason: Myc-Max is the conserved functional unit of c-Myc DNA binding. In Xenopus it is absent in the transcriptionally silent cleavage embryo, but it is the operative complex once zygotic transcription starts. The complex term is consistent with the human MYC review.

Summary: Xenopus c-Myc is expressed at the neural plate border before slug and is required for the formation of neural crest precursors; knockdown abolishes the NC precursors and their derivatives without changing proliferation or apoptosis, and the Myc target Id3 is required downstream.

Reason: Synthesis across lines of evidence. (1) Expression: c-myc is expressed in pluripotent blastula cells and then at the neural plate border, upstream of slug. (2) Activity: it is a Myc-Max E-box transcription factor whose target Id3 is itself required for NC progenitors. (3) Loss of function: knockdown removes NC precursors without changes in proliferation or apoptosis, and is rescued by c-Myc but not by Slug alone (per the full-text summary in the deep research). (4) Conservation: c-Myc is also required for the premigratory NC pool in chick. Network layer: Myc is a blastula-inherited competence/potency factor retained at the border. It is not a crest specifier such as Sox10 or FoxD3, so GO:0014036 neural crest cell fate specification does not apply. The role is captured by the proposed term neural crest progenitor maintenance (NTR), which replaces GO:0014029 (proposed for obsoletion; see projects/NEURAL_CREST_FORMATION_OBSOLETION.md). Participation: Myc acts as a transcription factor within the NC-forming cells; it is not a substrate or signal. Comparator check: X. laevis id3-a (Myc's target, same layer) and zic1 carry crest process terms by IMP. Mammalian and Xenopus c-Myc carry no neural crest term, but the family is not systematically absent: zebrafish mych carries GO:0014032 neural crest cell development by IMP (PMID:18446220). The c-Myc gap therefore reflects uncurated literature, not a convention. Homeolog caveat: the morpholino targets sequence shared by the c-myc genes and the rescue construct was c-Myc II-like. The annotation therefore applies equally to myc-b (P15171) and should not be read as myc-a-specific.