PDF(Pubmed)
Abstract：
Mutations in the human Ocular albinism type-1 gene OA1 are associated with abnormal retinal pigment epithelium (RPE) melanogenesis and poor binocular vision resulting from misrouting of ipsilateral retinal ganglion cell (iRGC) axons to the brain. We studied the latter using wild-type (WT) and Oa1-/- mouse eyes. At embryonic stages, the WT RPE-specific Oa1 protein signals through cAMP/Epac1-Erk2-CREB. Following CREB phosphorylation, a pCREB gradient extends from the RPE to the differentiating retinal amacrine and RGCs. In contrast to WT, the Oa1-/- RPE and ventral ciliary-margin-zone, a niche for iRGCs, express less pCREB while their retinas have a disrupted pCREB gradient, indicating Oa1\'s involvement in pCREB maintenance. Oa1-/- retinas also show hyperproliferation, enlarged nuclei, reduced differentiation, and fewer newborn amacrine and RGCs than WT retinas. Our results demonstrate that Oa1\'s absence leads to reduced binocular vision through a hyperproliferation-associated block in differentiation that impairs neurogenesis. This may affect iRGC axon\'s routing to the brain.
摘要：
人类眼白化病1型基因OA1的突变与异常的视网膜色素上皮（RPE）黑素生成和由于同侧视网膜神经节细胞（iRGC）轴突向大脑的错误路由而导致的双眼视力不良有关。我们使用野生型(WT)和Oa1-/-小鼠眼睛研究了后者。在胚胎阶段，WTRPE特异性Oa1蛋白通过cAMP/Epac1-Erk2-CREB发出信号。CREB磷酸化后，pCREB梯度从RPE延伸到区分视网膜无长突和RGC。与WT相比，Oa1-/-RPE和腹侧睫状缘区，iRGC的利基市场，表达较少的pCREB，而他们的视网膜有一个破坏的pCREB梯度，表示Oa1参与pCREB维护。Oa1-/-视网膜也表现出过度增殖，扩大的细胞核，减少分化，与WT视网膜相比，新生儿无长突和RGC较少。我们的结果表明，Oa1的缺失通过过度增殖相关的分化阻滞导致双眼视力降低，从而损害神经发生。这可能会影响iRGC轴突到大脑的路由。
