Hex (Strongylocentrotus purpuratus, UniProt A0A7M7R9J9) - curation notes

Identity

• UniProt A0A7M7R9J9 (A0A7M7R9J9_STRPU, unreviewed/TrEMBL, 317 aa) is an
  EnsemblMetazoa-derived "Homeobox domain-containing protein" with no literature
  RX line. Cross-references: RefSeq XP_781292.3 / XP_030841717.1, GeneID 575826
  and GeneID 115918645 (two loci in the current assembly, both named by NCBI
  "hematopoietically-expressed homeobox protein HHEX homolog"; checked via NCBI
  gene esummary, 2026-10-03), PANTHER PTHR24324:SF5 (official label, from
  interpro/panther/panther.obo: "HEMATOPOIETICALLY-EXPRESSED HOMEOBOX PROTEIN
  HHEX"), FunFam 1.10.10.60:FF:000721 "Hematopoietically-expressed homeobox
  protein HHEX". Single homeodomain at 186-246 (PROSITE PS50071) flanked by
  disordered N- and C-terminal regions, as in vertebrate HHEX.
• The GRN gene hex (Oliveri, Tu & Davidson 2008, where it is cited to the
  homeobox survey of Howard-Ashby et al. 2006, ref. 5) is the sea urchin HHEX
  orthologue: Saunders & McClay state that of the 13 PMC EMT transcription
  factors they studied, "12 of the 13 TFs are the sole member of their subfamily
  represented in the sea urchin genome" and PMID:24598159, i.e. hex is the
  single HHEX-class gene. Since A0A7M7R9J9 is the only HHEX-subfamily homeodomain
  protein in the S. purpuratus proteome, the accession and the GRN gene are the
  same gene. Confidence: high. The only residual caveat is that the two NCBI
  GeneIDs (575826, 115918645) with identical descriptions may be assembly
  duplicates (haplotypes) rather than two genes; the UniProt entry maps to both.
• Community symbol: Hex (hex, Sp-Hex, SpHex in the GRN literature).
• The homeobox survey that first characterized the S. purpuratus homeobox
  complement (including hex) is abstract-only in the cache:
  PMID:17055477. Its hex-specific data (WMISH in the micromere lineage) are not
  visible in the cached abstract.

Expression

• Zygotic, skeletogenic micromere / primary mesenchyme cell (PMC) lineage;
  listed among the genes expressed selectively in the large micromere-PMC
  lineage: PMID:30264451.
• Second, later domain in the oral non-skeletogenic mesoderm (NSM) after PMC
  ingression: PMID:23261933 PMID:23261933 The same cohort (gataC, ets1/2, hex, erg) characterizes sea star
  embryonic mesoderm PMID:23261933.

Place in the skeletogenic micromere GRN (Oliveri, Tu & Davidson 2008)

• Upstream: hex lies downstream of nuclear beta-catenin and pmar1 (the
  double-negative gate) and of the first-tier regulators, especially ets1 and
  alx1: PMID:30264451;
  PMID:30264451 (so the ets1 ->
  hex input is reported by one lab and not reproduced by the other).
• Position: the dynamic state-stabilization subcircuit immediately downstream
  of alx1/ets1/tbr/tel: PMID:18413610.
• Feedback: PMID:18413610 Hex is the hub of both loops.
• Outputs: PMID:18413610
• Differentiation genes: hex is one of the feed-forward drivers of the
  biomineralization gene battery PMID:18413610.
• Phenotype of hex MASO (the key loss-of-function result): skeleton-minus with
  normal ingression, i.e. a differentiation rather than an EMT defect in S.
  purpuratus: PMID:18413610; PMID:18413610
• Interpretation of the loop by Ettensohn's group: PMID:30264451 PMID:30264451

Lytechinus variegatus EMT data (Saunders & McClay 2014; not S. purpuratus)

• LvHex was cloned from the Sp annotation and knocked down with two MASOs;
  hex is one of the 10 downstream PMC TFs required for EMT: PMID:24598159 Specifically it is a terminal node
  of the apical-constriction and motility sub-circuits: PMID:24598159 PMID:24598159 In the Lv PMC GRN "snail
  regulates erg and erg regulates hex".
• This contrasts with the S. purpuratus result that hex morphants ingress
  normally (Oliveri 2008, Fig. 3C-E). Because of the species difference and the
  conflicting ingression phenotype, no EMT annotation is proposed for the Sp
  gene product; recorded as a question.

Curation decisions

• All seven GOA rows are electronic (IEA InterPro/UniRule, IBA PAINT on the HHEX
  node PTN001963821). The IBA rows (sequence-specific cis-regulatory DNA
  binding, regulation of Pol II transcription, cell differentiation) are
  consistent with the GRN data and were accepted / kept as non-core. Generic
  DNA binding (IEA) -> MODIFY to sequence-specific DNA binding. Generic
  regulation of DNA-templated transcription -> KEEP_AS_NON_CORE.
• NEW (all IMP from Oliveri 2008 morpholino/QPCR and phenotype data):
  GO:0045944 positive regulation of transcription by RNA polymerase II (hex
  drives erg, tgif, foxo and the differentiation genes), GO:0001710 mesodermal
  cell fate commitment (state lockdown of the skeletogenic mesenchyme), and
  GO:0070169 positive regulation of biomineral tissue development (skeleton-
  minus phenotype with normal ingression). No activator MF (GO:0001228) because
  no cis-regulatory or binding assay exists for Sp-Hex; the sign is inferred
  from perturbation only.
• gocams/index.tsv has no entry for A0A7M7R9J9.
• Sibling reviews with the same subcircuit: Erg (genes/STRPU/Erg), Ets1, Alx1.