Molecular control of vertebrate retinal development
`From cell fate determination to synapse formation`
Takahisa Furukawa, M.D. & Ph. D.
Department of Developmental Biology, Osaka Bioscience Institute
The retinal photoreceptor cells play a primal and central role in the phototransduction system. They are susceptible to deterioration in human retinal diseases, which lead to severe visual impairment. To understand the molecular mechanism of photoreceptor development is an interesting and important issue. We have been demonstrated that transcription factors, Otx2 and Crx play critical roles in retinal photoreceptor development. We previously reported that the cell fate s of both rod and cone photoreceptors are converted to that of amacrine-like cells in the Otx2 conditional knockout (CKO) mouse line, which express C re recombinase in developing photoreceptors. We supposed that the transc r ipts from various genes , which are important for phot o receptor development, maintenance a nd function , are relatively down-regulated in the Otx2 CKO retina compared with those of wild-type retina. In order t o identify genes which regulate photoreceptor development , we performed microarray analysis comparing the retinal gene expression profile between wild-type and Otx2 CKO mouse retinas.
In this screen, we identified various Otx2 downstream factors possibly involved in photoreceptor development. Among these genes, we identify pikachurin, a novel extracellular matrix-like retinal protein. Pikachurin null mutant mice display improper apposition of the bipolar terminus to the ribbon synapse, resulting in alterations in synaptic signal transmission and visual function as detected by electroretinogram. We observed co-localization of pikachurin with dystrophin-glycoprotein complex (DGC) molecules and direct binding of pikachurin with a-dystroglycan, an extracellular component of DGC. Together, our results identify a novel dystroglycan ligand, pikachurin, and demonstrate its essential role in the precise interactions between the photoreceptor ribbon synapse and the bipolar terminus.