Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
Cell Rep. 2024 Jun 25;43(6):114291. doi: 10.1016/j.celrep.2024.114291. Epub 2024 May 31.
Atoh7 is transiently expressed in retinal progenitor cells (RPCs) and is required for retinal ganglion cell (RGC) differentiation. In humans, a deletion in a distal non-coding regulatory region upstream of ATOH7 is associated with optic nerve atrophy and blindness. Here, we functionally interrogate the significance of the Atoh7 regulatory landscape to retinogenesis in mice. Deletion of the Atoh7 enhancer structure leads to RGC deficiency, optic nerve hypoplasia, and retinal blood vascular abnormalities, phenocopying inactivation of Atoh7. Further, loss of the Atoh7 remote enhancer impacts ipsilaterally projecting RGCs and disrupts proper axonal projections to the visual thalamus. Deletion of the Atoh7 remote enhancer is also associated with the dysregulation of axonogenesis genes, including the derepression of the axon repulsive cue Robo3. Our data provide insights into how Atoh7 enhancer elements function to promote RGC development and optic nerve formation and highlight a key role of Atoh7 in the transcriptional control of axon guidance molecules.
Atoh7 在视网膜祖细胞 (RPC) 中瞬时表达，是视网膜神经节细胞 (RGC) 分化所必需的。在人类中， ATOH7 上游远端非编码调控区的缺失与视神经萎缩和失明有关。在这里，我们在小鼠中对 Atoh7 调控景观对视网膜发生的功能进行了研究。Atoh7 增强子结构的缺失导致 RGC 缺乏、视神经发育不良和视网膜血管异常，与 Atoh7 的失活表型相似。此外， Atoh7 远程增强子的缺失还会影响同侧投射的 RGC，并破坏到视觉丘脑的正确轴突投射。Atoh7 远程增强子的缺失也与轴突发生基因的失调有关，包括轴突排斥信号 Robo3 的去抑制。我们的数据提供了对 Atoh7 增强子元件如何促进 RGC 发育和视神经形成的深入了解，并强调了 Atoh7 在轴突导向分子转录控制中的关键作用。
