Genomic stability in retinal development and degeneration

While genetic changes and mutations are crucial for evolution, maintenance of genomic stability is crucial for proper development and disease prevention. DNA replication as well as genotoxic agents may cause replicative stress leading to genomic instability. Prevention of replicative stress requires the ataxia telangiectasia and Rad3-related protein (ATR) kinase and its partner ATRIP (ATR-interacting protein). Mutations of these genes in humans lead to Seckel syndrome, a disorder characterized by growth impairment prior to birth, microcephaly and mental retardation. The high replicative index during neurogenesis and the unique metabolism of long-live neural cells have been proposed to contribute to the elevated sensitivity of the central nervous system (CNS) to genomic stability. To study the roles of Atr-Atrip signaling complex in replicative stress during CNS development in vivo, we first characterized how neural progenitor cells (NPC) respond to replicative stress induced by genotoxic agents. Hydroxyurea (HU) treatment of retinal explants induced DNA damage, checkpoint activation and cell death. Pharmacological inactivation of Atr-Atrip signaling increased the sensitivity to replicative stress. To evaluate ATR-ATRIP complex roles in vivo, we generated transgenic mice in which Atrip was inactivated specifically in the brain and/or in the retina. Loss of Atrip in NPCs resulted in developmental defects, microcephaly and postnatal lethality. Atrip inactivation in the retina led to DNA damage accumulation and increased cell death during embryogenesis. Severe dysplasia, lamination defects and neurodegeneration were observed in Atrip-deficient adult retinas. In addition, we found direct evidence of neuroinflammation and microglial activation during embryonic cerebral cortex development. These findings demonstrate that ATR-ATRIP signaling is essential for neural progenitor cells survival and for CNS histogenesis in vivo, contributing to a better understanding of the roles of ATR and ATRIP in syndromes associated with replicative stress and genomic instability. None.