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.

An Eye in the Replication Stress Response: Lessons From Tissue-Specific Studies in vivo

“…Although RSR has been extensively studied in various models, the mechanisms of the ATR activation and, therefore, the exact roles of ATR regulators in unchallenged replication in vivo are still not completely understood. For example, it was clear that ATR protein stability and function depend on its interaction with ATRIP in human cells ( Cortez et al, 2001 ), however, prior to our recent work ( Matos-Rodrigues et al, 2020a , b ) ATRIP function had not been investigated in vivo . Moreover, while ETAA1 plays an essential role in an ATR-regulated S-G2 checkpoint in immortalized cells ( Saldivar et al, 2018 ), ETAA1 null mice show a mild phenotype of partial embryonic lethality ( Miosge et al, 2017 ).…”

“…Microphthalmia has been reported in both Seckel and Nijmegen breakage syndromes ( Figure 1B ). Studies in animal models (discussed in the next sections) suggested that defective cell proliferation and increased cell death may be the cause of microphthalmia following the inactivation of RSR genes ( Yang et al, 2006 ; Rodrigues et al, 2013 ; Matos-Rodrigues et al, 2020a , b ). However, the mechanisms driving eye growth defects in syndromes caused by mutations in RSR-genes are far from being completely understood.…”

“…We have also evaluated the effects of RSR inactivation in the mouse retina. ATRIP loss in embryonic retinal progenitor cells induces DNA damage accumulation and cell death, leading to lamination defects, photoreceptor degeneration and loss of vision ( Matos-Rodrigues et al, 2020b ). A previous study revealed photoreceptor degeneration in mice carrying an Atr hypomorphic mutation ( Valdes-Sanchez et al, 2013 ).…”

“…In contrast to the lens, inactivation of Trp53 rescues the cell death of retinal progenitor cells, neurodegeneration and visual impairment caused by ATRIP loss, indicating that TRP53-dependent apoptosis is the driver of retinal malformations caused by Atrip inactivation ( Matos-Rodrigues et al, 2020b ). These findings reinforced the existence of tissue-specific effects of RSR inactivation in the developing eye.…”

“…In retinal progenitor cells, Atrip inactivation also leads to DNA damage accumulation and cell death. However, retinal development is not completely impaired by the slight modifications in proliferation and differentiation caused by defective RSR ( Matos-Rodrigues et al, 2020b ). These results suggest that lens progenitor cells are more sensitive to RSR inactivation than retinal ones and point to a different synergy between Atrip and Trp53 when comparing retinal and lens progenitors.…”