Retinal determination network module

The conserved gene regulatory network that specifies eye identity in bilaterians. A Pax6 paired/homeodomain selector transcription factor initiates the program and induces expression of a Six-family homeodomain transcription factor (Sine oculis / SIX) and the Eyes absent (EYA) cofactor. EYA, a nuclear transcriptional coactivator with intrinsic protein phosphatase activity, binds SIX proteins and converts SIX-dependent repression into activation; Dachshund (DACH), a Ski/Sno-related nuclear cofactor, also complexes with EYA. The factors cross-regulate one another in positive feedback loops, so the network behaves as an interlocked circuit rather than a linear hierarchy. Misexpression of the Pax6, Six/Eya or Dachshund components can induce ectopic eye tissue in Drosophila, and the vertebrate orthologs (PAX6, SIX3/SIX6, EYA, DACH) act with the same epistatic logic in optic vesicle, retina and lens development.

Boundary: the module covers the transcriptional core of eye-field / eye-disc specification (Pax6, Six, Eya, Dach). Upstream inputs (Hedgehog, Dpp/BMP, Notch and EGFR signalling; Hox repression of eyeless outside the head), downstream neurogenesis (atonal/ATOH7 activation) and photoreceptor differentiation are context, not parts. In Drosophila the Pax6 role is split between twin of eyeless (toy), which directly activates the eye-specific enhancer of eyeless (ey), and ey itself; mammals have a single PAX6, so both are modelled as representatives of one Pax6 family annoton. Insects use So (Six1/2 subfamily) in the eye, while vertebrate eye-field specification relies chiefly on the Six3/6 subfamily (fly Optix); both are represented under one Six-family annoton. Gene reviews now exist for all representatives (so, eya, dac, SIX3, SIX6, EYA1, DACH1); the fly dac representative is an unreviewed UniProt entry. EYA1 is used as the mammalian Eya exemplar for the conserved coactivator/phosphatase activities only: its loss-of-function roles are in ear, kidney and branchial arches (branchio-oto-renal syndrome), not retinal specification, so the eye-development process on the Eya annoton rests on Drosophila eya. Human DACH1 is a transcriptional corepressor (a child of the annoton's coregulator term) with reported direct DNA binding not shown for fly Dac. Specification of animal organ identity (GO:0010092) is deliberately not used as a module concept: in GOA it is carried only by appendage/segment identity selectors (Ubx, Dll, ss, hth, Tbr1) and by no Pax6, Six, Eya or Dach ortholog in any species, so eye identity is represented through eye development instead.