SIX3 notes

Automated deep research was unavailable for this session (falcon 402, OpenAI 401); no
-deep-research-<provider>.md file was generated. These notes come from cached publications,
the UniProt record and QuickGO annotation lookups of mouse Six3 (Q62233).

Molecular function

• Homeodomain TF of the Six3/6 (Optix) subfamily; does not pair with EYA. Instead it recruits Groucho/TLE:
  PMID:12050133;
  PMID:12050133.
• Human SIX3 binds TLE1 and AES via the Six domain (and the TLE WD domain):
  PMID:12441302.
• HPE eh1-motif variants abolish human SIX3 corepressor activity:
  PMID:18791198.
• Direct repression of Wnt1 (mouse): PMID:12569128
• Direct repression of Wnt8b for neuroretina specification: PMID:20890044.
• Context-dependent activator: Shh SBE2 enhancer PMID:18836447;
  Pax6/Sox2 in lens ectoderm PMID:17066077; rhodopsin PMID:17666527.
• Non-transcriptional: binds geminin, competing with Cdt1 PMID:14973488.

Biological roles

• Forebrain: Six3-null mice lack telencephalon/rostral diencephalon (Wnt1 expansion) PMID:12569128; haploinsufficiency fails to activate Shh, causing HPE PMID:18694563.
• Eye: medaka knockdown -> no forebrain/eyes; proximodistal optic vesicle patterning; cooperation with Pax6 PMID:12163408.
• Lens induction via Pax6 [PMID:17066077, PMID:12072567]; pituitary with Hesx1 PMID:18775421; ependymal maturation PMID:22071110.
• Human disease: HPE2 PMID:10369266; 89% of tested variants LOF PMID:18791198.

Review decisions

• Core MF: GO:0001227 repressor activity (NEW), GO:0001222 corepressor binding, GO:0000981 (activator in context).
• Visual perception REMOVE (IEA) / over-annotated (TAS). Protein binding (NR4A3) -> GO:0061629.
• Lens fiber apoptosis, apoptotic process in development, neuroblast migration, lens fiber differentiation: over-annotations (indirect).
• Module retinal_determination_network annoton (GO:0000981 in eye development) is consistent, but SIX3 is
  better described as a repressor (GO:0001227) and, unlike fly So, does not act via EYA; module role text emphasises the So/Eya partnership.