Tcf (SpTcf/Lef, Q9Y0B2) — curation notes

Identity

• UniProt Q9Y0B2, "HMG protein Tcf/Lef" (EMBL AAD45010.1), cloned by Huang et al. 2000 from
  Strongylocentrotus purpuratus as SpTcf/Lef. The record's single RX reference is PMID:10664150.
  Domains: N-terminal beta-catenin-binding region (InterPro IPR013558, Pfam PF08347), HMG box
  (IPR009071, residues 316-384), TCF/LEF family signature (IPR024940). PANTHER PTHR10373:SF38.
• The community GRN name is simply Tcf (also Tcf1 in Minokawa et al. 2005). It is the only
  Tcf/Lef-family gene in the sea urchin, so the accession and the GRN node are the same gene.

What the gene does

SpTcf/Lef is the HMG-box transcription factor that transduces the maternal beta-catenin signal
into transcription in the vegetal half of the embryo. Its expression peaks when beta-catenin
nuclearizes in vegetal blastomeres, and a dominant-negative form phenocopies the loss of
nuclear beta-catenin PMID:10664150.

Nuclear beta-catenin itself is required for all vegetal fates PMID:9847248, and Tcf is its nuclear effector: dominant-negative TCF animalizes,
activated TCF vegetalizes, and all of beta-catenin's axial activity runs through TCF
[PMID:10625549 "We show that expression of a dominant negative TCF results in a classic
"animalized" embryo. In contrast, microinjected RNA encoding an activated TCF produces a highly
"vegetalized" embryo."; "We also provide evidence indicating that all of beta-catenin's activity
in patterning the sea urchin AV axis is mediated by TCF."]. The Vonica et al. abstract does not
state which sea urchin species was used; treat as corroborating, not S. purpuratus-specific.

The activator/repressor switch

In the animal half, where beta-catenin is not nuclear, Tcf bound by the co-repressor Groucho
silences the endomesoderm regulatory genes; nuclear beta-catenin competes Groucho off Tcf and
converts it to an activator. This was shown in Lytechinus variegatus [PMID:15708573 "Interaction
assays demonstrate that LvGroucho interacts with Tcf via both the Q and the WD domains of the
protein. LvGroucho interacts with Tcf to antagonize the expression of key endomesoderm regulatory
genes."; "LvGroucho functionally competes with beta-catenin for Tcf binding, and this competitive
mechanism regulates one of the earliest steps in the initiation of the sea urchin endomesoderm
GRN"]. In S. purpuratus the same dual behaviour is written into the wnt8 cis-regulatory system:
Tcf sites are needed for endomesodermal activation, and in a second module they repress ectopic
expression in the prospective ectoderm [PMID:16289024 "The Tcf1/beta-catenin and Blimp1/Krox
inputs are both necessary for normal endomesodermal expression mediated by this cis-regulatory
module"; "In a second regulatory region, which initiates expression in micromere and macromere
descendant cells early in cleavage, Tcf1 sites act to repress ectopic transcription in
prospective ectoderm cells."]. Peter & Davidson formalize this as the Tcf 'X, 1-X' processor and
show the same Tcf sites later extinguish the endoderm GRN in mesoderm precursors
[PMID:21623371 "the same Tcf sites that are used to initiate the endoderm GRN in the veg2
lineage are used again to extinguish it in mesoderm precursors"; "A possible explanation is that
in cells receiving Notch signalling, the availability of nuclear β-catenin is reduced, leading to
Tcf/Groucho-mediated repression."].

Place in the endomesoderm GRN

• Micromere / skeletogenic lineage: beta-catenin/Tcf plus Otx activate pmar1, the top of the
  double-negative gate [PMID:18413610 "The pmar1 genes are activated by the β-catenin/Tcf
  transcription complex plus Otx, i.e., by two of the micromere-specific inputs just enumerated
  ( 25 , 30 )."; "Dsh regionally prevents the degradation of cytoplasmic β-catenin ( 27 ), which
  transits to the nucleus, forming an active complex with the Tcf transcription factor."].
• Wnt8 community-effect loop: wnt8 needs beta-catenin/Tcf and Blimp1 inputs, so Tcf both
  receives and drives the Wnt8 signal [PMID:18413610 "the inputs required for its expression in
  the micromere lineage are Blimp1 and β-catenin/Tcf"; PMID:19104065 "the wnt8 gene requires
  inputs from both β-catenin/Tcf (i.e., from the same signal transduction system that it
  activates) and from Blimp1 factor for expression"].
• veg2 endoderm: most of the eight early endoderm regulatory genes are under cis-regulatory Tcf
  control PMID:21623371.
• Timing / shutdown in mesoderm: Tcf activity is required early but must be turned off in the
  mesodermal lineage by Notch-induced NLK (shown in Paracentrotus lividus) PMID:17038519.

Curation decisions

• GOA has three electronic rows (DNA binding, nucleus, Wnt signaling pathway). All are
  consistent with the literature. DNA binding and nucleus are accepted; the generic Wnt term is
  narrowed to canonical (beta-catenin-dependent) Wnt signaling, since Tcf is the transcriptional
  endpoint of that branch.
• NEW: activator activity (GO:0001228, IMP, Huang 2000) and repressor activity (GO:0001227,
  IDA, Minokawa 2005) - both signs are demonstrated and both are the biology of the switch.
  Canonical Wnt signaling pathway (GO:0060070, IMP). Endodermal (GO:0001714) and mesodermal
  (GO:0007501) cell fate specification (IMP): Tcf itself performs the transcriptional step that
  turns on pmar1, wnt8, blimp1 and the veg2 endoderm genes, so it passes the participation test;
  its vertebrate orthologues carry the equivalent germ-layer terms.
• Not proposed: beta-catenin binding and Groucho binding. Direct binding has been assayed only
  for the Lytechinus protein (Groucho) or inferred from LiCl/dominant-negative behaviour; no
  S. purpuratus binding assay is cached. Recorded as a knowledge gap.
• gocams/index.tsv has no S. purpuratus Tcf model.