Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of Atrip-Seckel syndrome

Abstract

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.