a regulatory loop involving pax6, mitf, and wnt signaling controls retinal pigment epithelium development监管涉及pax6循环、mitf和wnt信号控制视网膜色素上皮细胞的发展.pdfVIP

A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium Development 1 1¤a 1 1¤b 1 Kapil Bharti *, Melanie Gasper , Jingxing Ou , Martha Brucato , Katharina Clore-Gronenborn , James Pickel2, Heinz Arnheiter1 1 Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Transgenic Core Facility, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America Abstract The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development in vertebrates. Here we show in mice that the transcription factor PAX6, well-known for its retina- promoting activity, also plays a crucial role in early pigment epithelium development. This role is seen, however, only in a background genetically sensitized by mutations in the pigment cell transcription factor MITF. In fact, a reduction in Pax6 gene dose exacerbates the RPE-to-retina transdifferentiation seen in embryos homozygous for an Mitf null allele, and it induces such a transdifferentiation in embryos that are either heterozygous for the Mitf null allele or homozygous for an RPE–specific hypomorphic Mitf allele generated by targeted mutation. Conversely, an increase in Pax6 gene dose interferes with transdifferentiation even in homozygous Mitf null embryos. Gene expression analyses show that, together with MITF or its paralog TFEC, PAX6 suppresses the expression of Fgf15 and Dkk3. Explant culture experiments indicate that a combination of FGF and DK