Regulation of by DLX1 and DLX2 is required for retinal ganglion cell differentiation in the vertebrate retina.

Regulated retinal ganglion cell (RGC) differentiation and axonal guidance is required for a functional visual system. Homeodomain and basic helix-loop-helix transcription factors are required for retinogenesis, as well as patterning, differentiation and maintenance of specific retinal cell types. We hypothesized that , and homeobox genes function in parallel intrinsic pathways to determine RGC fate and therefore generated // triple-knockout mice. A more severe retinal phenotype was found in the //-null retinas than was predicted by combining features of the single- and / double-knockout retinas, including near total RGC loss with a marked increase in amacrine cells in the ganglion cell layer. Furthermore, we discovered that DLX1 and DLX2 function as direct transcriptional activators of expression. Knockdown of expression in primary embryonic retinal cultures and gain of function strongly support that DLX2 is both necessary and sufficient for expression We suggest that ATOH7 specifies RGC-committed progenitors and that and function both downstream of ATOH7 and in parallel, but cooperative, pathways that involve regulation of expression to determine RGC fate.