A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium Development

• DOI: 10.1371/journal.pgen.1002757
• Publication Date: 2012-07-06T01:26:53Z
• Authors: Kapil Bharti; Melanie Gasper; Jingxing Ou; Martha Brucato; Katharina Clore-G...; James Pickel; Heinz Arnheiter
• Keywords: Microphthalmia-associated transcription factor; PAX6; Transdifferentiation; Null allele

The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development vertebrates. Here we show mice that transcription factor PAX6, well-known for its retina-promoting activity, also plays crucial role development. This seen, however, only background genetically sensitized by mutations cell MITF. In fact, reduction Pax6 gene dose exacerbates RPE-to-retina transdifferentiation seen embryos homozygous an Mitf null allele, it induces such are either heterozygous allele or RPE–specific hypomorphic generated targeted mutation. Conversely, increase interferes with even embryos. Gene expression analyses that, together MITF paralog TFEC, PAX6 suppresses Fgf15 Dkk3. Explant culture experiments indicate combination FGF DKK3 promote formation inhibiting canonical WNT signaling stimulating retinogenic genes, including Six6 Vsx2. Our results demonstrate conjunction Mitf/Tfec acts as anti-retinogenic factor, whereas genes pro-retinogenic factor. suggest careful manipulation regulatory circuit may facilitate generation cells from embryonic induced pluripotent stem cells.