Seckel syndrome is a type of microcephalic primordial dwarfism (MPD) that is characterized by growth retardation and neurodevelopmental defects, including reports of retinopathy. Mutations in key mediators of the replication stress response, the mutually dependent partners ATR or ATRIP, are among the known causes of Seckel syndrome. However, it remains unclear how their deficiency disrupts the development and function of the central nervous system (CNS). Here, we investigate the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons does not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) leads to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we show that RPCs lacking functional ATRIP exhibit higher levels of replicative stress and accumulate endogenous DNA damage, that is accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevents apoptosis of Atrip-deficient progenitor cells and is sufficient to rescue retinal dysplasia, neurodegeneration and vision loss. Together, these results reveal an essential role of ATRIP-mediated replication stress response in CNS development and suggest that the TRP53-mediated apoptosis of progenitor cells may contribute to retinal malformations in Seckel syndrome and other MPD disorders.

中文翻译：

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在 Atrip-Seckel 综合征小鼠模型中，祖细胞死亡导致视网膜发育不良和神经元变性。


塞克尔综合征是一种小头型原始侏儒症 (MPD)，其特征是生长迟缓和神经发育缺陷，包括视网膜病变的报道。复制应激反应的关键介质（相互依赖的伙伴 ATR 或 ATRIP）的突变是 Seckel 综合征的已知原因之一。然而，目前尚不清楚它们的缺乏如何破坏中枢神经系统（CNS）的发育和功能。在这里，我们研究了发育中的神经视网膜的不同细胞群中 ATRIP 缺陷的细胞和分子后果。我们发现光感受器神经元中Atrip的条件失活不会影响其存活或功能。相比之下，视网膜祖细胞 (RPC) 中的Atrip缺陷会导致严重的层压缺陷，进而导致继发性感光器变性和视力丧失。此外，我们发现缺乏功能性 ATRIP 的 RPC 表现出更高水平的复制应激并积累内源性 DNA 损伤，同时伴随着 TRP53 的稳定。值得注意的是， Trp53的失活可防止Atrip缺陷祖细胞的凋亡，并足以挽救视网膜发育不良、神经变性和视力丧失。总之，这些结果揭示了 ATRIP 介导的复制应激反应在 CNS 发育中的重要作用，并表明 TRP53 介导的祖细胞凋亡可能导致 Seckel 综合征和其他 MPD 疾病中的视网膜畸形。