Selective induction of retinal photoreceptors out of iris pigment epithelial cells.

我们之前报道过Otx2对于光感受器细胞命运的决定至关重要(Nishida等，Nat. Neurosci。， 6,1255 -1263, 2003)，然而，尽管有报道称Otx2在出生后视网膜双极细胞和光感受器中表达，但它在出生后视网膜发育中的功能作用仍不清楚。在本研究中，我们首先通过分析Otx2在光感受器终末分化中的作用；Crx双敲除小鼠。在Otx2 ^ < + / - >;与Crx^<-/->视网膜相比，Crx^<-/->视网膜的光感受器变性和光感受器特异性基因下调更为突出，表明Otx2在光感受器的终末分化中发挥了作用。此外，双极细胞在Otx2^<+/->中减少；Crx^<-/->视网膜，提示Otx2也参与视网膜双极细胞发育。为了进一步研究Otx2在双极细胞发育中的作用，我们建立了一个出生后双极细胞特异性Otx2条件敲除小鼠系。免疫组化分析显示，成熟双极细胞的标志蛋白激酶C在视网膜中的表达明显下调。视网膜电图显示，由于Otx2消融，视网膜双极细胞的电生理功能受损。这些数据表明，Otx2在视网膜感光细胞和双极细胞的成熟中起功能作用。我们在分子和细胞生物学（27页8318-8329,2007）上报道了这些结果。

We previously reported that Otx2 is essential for photoreceptor cell fate determination (Nishida, et. al., Nat. Neurosci., 6, 1255-1263, 2003), however, the functional role of Otx2 in postnatal retinal development is still unclear although it has been reported to be expressed in retinal bipolar cells and photoreceptors at postnatal stages. In this study, we first examined the roles of Otx2 in the terminal differentiation of photoreceptors by analyzing Otx2; Crx double-knockout mice. In Otx2^<+/->; Crx^<-/-> retinas, photoreceptor degeneration and downregulation of photoreceptor-specific genes were much more prominent than in Crx^<-/-> retinas, suggesting that Otx2 has a role in the terminal differentiation of the photoreceptors. Moreover, bipolar cells decreased in the Otx2^<+/->; Crx^<-/-> retina, suggesting that Otx2 is also involved in retinal bipolar-cell development. To further investigate the role of Otx2 in bipolar-cell development, we generated a postnatal bipolar-cell-specific Otx2 conditional-knockout mouse line. Immunohistochemical analysis of this line showed that the expression of protein kinase C, a marker of mature bipolar cells, was significantly downregulated in the retina. Electroretinograms revealed that the electrophysiological function of retinal bipolar cells was impaired as a result of Otx2 ablation. These data suggest that Otx2 plays a functional role in the maturation of retinal photoreceptor and bipolar cells. We reported these results in Molecular and Cellular Biology (27 p 8318-8329, 2007).