Gcm (Strongylocentrotus purpuratus, UniProt Q8MMJ4) - curation notes

Identity

• UniProt Q8MMJ4 (Q8MMJ4_STRPU, unreviewed/TrEMBL, 794 aa) is the S. purpuratus
  Glial cells missing-like protein deposited by the Davidson lab from the 12 h
  endomesoderm cDNA library (EMBL AAM53250.1, RefSeq NP_999826.1, GeneID 378470).
  Its single RX line is PMID:12027439 (Ransick et al. 2002), the differential
  macroarray screen that discovered Spgcm. Community symbol: gcm / Gcm
  (older papers Spgcm, SpGcm). No identity doubt: this is the single sea
  urchin gcm gene used in all Davidson-lab GRN work.
• Domain architecture (UniProt FT): GCM DNA-binding domain at residues 50-208
  (PROSITE PS50807, Pfam PF03615); three MobiDB-lite disordered regions; the
  more 3' exons encode the trans-activation domains
  PMID:22509525.
  PANTHER PTHR12414 / PTHR12414:SF8 (labels not written from memory here).
• The GCM consensus binding site ATGCGGRY is used in cis-regulatory work on this
  gene PMID:22509525.

Place in the endomesoderm GRN

Gcm is the immediate transcriptional target of Delta/Notch signalling from the
skeletogenic micromeres and the top-level regulator of the aboral
non-skeletogenic mesoderm (NSM) / pigment cell regulatory state.

• Discovery and expression: found among transcripts sharply reduced by
  cadherin-mRNA blockade of nuclear beta-catenin
  PMID:12027439.
  Also recovered independently in a pigment-cell-specific differential screen
  and shown by WMISH to be pigment-cell specific
  [PMID:12925586 "This group of clones contained sequences highly similar to: the transcription factor glial cells missing (gcm); the polyketide synthase gene cluster (pks-gc)"; "it was shown that these genes are specifically expressed in pigment cells"].
• Input (Delta/Notch via Su(H)): three cis-regulatory modules identified; a
  conserved paired Su(H) site plus a lone site in the middle module both drive
  expression in Delta-receiving SMC precursors and repress it elsewhere
  PMID:16925988.
  gcm is the first gene switched on by Delta signalling in veg2
  [PMID:22306924 "gcm was previously shown to be a direct cis-regulatory target of the Nic/Su(H) complex (Ransick and Davidson, 2006), and is the first gene to become activated by D/N signaling."; "Only these cells are contiguous to the Delta source on which gcm expression is dependent."].
• Spatial repression: Alx1 keeps gcm out of the skeletogenic micromere lineage
  PMID:18413610,
  and FoxA keeps it out of the veg2 endoderm
  PMID:17038513.
  Later, Not clears gcm from the oral NSM so that gcm becomes strictly aboral
  PMID:23261933.
• Output, early phase (specification): gcm morpholino gives larvae with no pigment cells
  [PMID:16925988 "Here, we show that microinjection of a spgcm antisense morpholino oligonucleotide results in larvae without pigment cells."; "These results confirm that this gene is required for pigment cell specification."].
  gcm is the pioneer of the aboral NSM regulatory state
  PMID:23261933.
• Output, direct targets: gataE is a direct Gcm target and Gcm is the
  Notch-dependent feed-forward input into gataE
  PMID:23261933
  PMID:22306924.
  pks (echinochrome polyketide synthase) is a direct target via Gcm sites in
  its -1.5 kb cis-regulatory region
  PMID:20122918.
  Gcm MASO knocks down the whole pigment differentiation battery
  [PMID:23261933 "As expected, Gcm MASO causes severe decreases in transcript levels of the differentiation genes bpnt, dopt, fmo, papss, pks, and sult."; "Gcm provides a direct input into pigment cell differentiation genes, which begin to be expressed even before gastrulation"].
• Output, late phase (self-sustaining loop): a late cis-regulatory module takes
  over from mesenchyme blastula; its two critical elements are Gcm and Six1 sites
  (autoregulation plus gcm-gataE-six1 feedback)
  [PMID:22509525 "Cis-perturbation analyses reveal that the two critical elements within this late module are consensus matches to Gcm and Six1 binding sites."; "The self-sustaining expression of gcm that the late module promotes effectively locks down the pigment cell fate."; "Gcm is required in veg2 progeny during late cleavages for the early phase of pigment cell precursor specification."].
• Sufficiency (synthetic rewiring): forcing gcm under tbr control in
  skeletogenic cells converts them to pigment cells and up-regulates pks while
  repressing alx1/ets1/tbr
  [PMID:22238426 "The result of reengineering the regulatory circuitry in this way was to divert the developmental program of these cells from skeletogenesis to pigment cell formation, confirming a direct prediction of the GRN."; "Both Delta/Notch signaling and Gcm translation are absolutely required for pigment cell specification"].
  The repression of skeletogenic genes is indirect (probably via ets1) and is
  not annotated here. Cross-species confirmation in other euechinoids:
  [PMID:27046223 "We confirmed previous results by demonstrating that gcm is involved in pigment cell differentiation."; "gcm functions in skeletogenic fate repression"].

Annotation decisions (journal)

• Electronic MF/CC rows (GO:0000981, GO:0000978, GO:0001228, GO:0003677, nucleus)
  are consistent with the cis-regulatory evidence (Gcm sites required in pks and
  in the gcm late module; direct activation of gataE) and are accepted.
• GO:0042063 gliogenesis (IBA, from Drosophila gcm/gcm2 and mouse Gcm1): removed.
  The Drosophila glial function is lineage-specific; vertebrate Gcm1/Gcm2 act in
  placenta/parathyroid, and sea urchin gcm is expressed exclusively in mesodermal
  pigment cell precursors and never in neural tissue, so the target lies outside
  any clade for which gliogenesis can be inferred.
• NEW: GO:0001228 (IDA, pks and gcm late-module site mutagenesis), GO:0000978
  (IDA), GO:0045944 (IDA/IMP), GO:0007501 mesodermal cell fate specification (IMP:
  MASO loss, synthetic gain), GO:0050942 positive regulation of pigment cell
  differentiation (IMP/IDA). Indirect skeletogenic repression and oral-NSM
  repression (via GataE) are not annotated.
• gocams/index.tsv contains no entry for this gene.