Abstract
Genomic instability in the central nervous system (CNS) is associated with defective neurodevelopment and neurodegeneration. Congenital human syndromes that affect the CNS development originate from mutations in genes of the DNA damage response (DDR) pathways. RINT1 (Rad50-interacting protein 1) is a partner of RAD50, that participates in the cellular responses to DNA double-strand breaks (DSB). Recently, we showed that Rint1 regulates cell survival in the developing brain and its loss led to premature lethality associated with genomic stability. To bypass the lethality of Rint1 inactivation in the embryonic brain and better understand the roles of RINT1 in CNS development, we conditionally inactivated Rint1 in retinal progenitor cells (RPCs) during embryogenesis. Rint1 loss led to accumulation of endogenous DNA damage, but RINT1 was not necessary for the cell cycle checkpoint activation in these neural progenitor cells. As a consequence, proliferating progenitors and postmitotic neurons underwent apoptosis causing defective neurogenesis of retinal ganglion cells, malformation of the optic nerve and blindness. Notably, inactivation of Trp53 prevented apoptosis of the RPCs and rescued the generation of retinal neurons and vision loss. Together, these results revealed an essential role for TRP53-mediated apoptosis in the malformations of the visual system caused by RINT1 loss and suggests that defective responses to DNA damage drive retinal malformations.
Highlights
Several human diseases that affect the central nervous system (CNS) originate from mutations in genes of the DNA damage response (DDR) pathways (Jackson and Bartek, 2009; McKinnon, 2017)
To investigate RINT1 function during retinogenesis, we used a previously generated Rint1 floxed mice (Grigaravicius et al, 2016) and crossed with an α-Cre mouse line (Marquardt et al, 2001) that leads to Rint1 genetic inactivation in retinal progenitor cells (RPCs)
No alteration in the number of neurons in the ganglion cell layer (GCL) was detected at E15.5; during postnatal stages, fewer neurons occupy the GCL of Rint1α-Cre retinas (Figure 4E). These findings suggest that the defective neurogenesis and optic nerve hypoplasia of Rint1α-Cre mice is caused by the apoptosis of both postmitotic neurons and committed RPCs
Summary
Several human diseases that affect the central nervous system (CNS) originate from mutations in genes of the DNA damage response (DDR) pathways (Jackson and Bartek, 2009; McKinnon, 2017). Rint inactivation in the developing brain is lethal, causes massive apoptosis of neural progenitor cells, and was associated with DNA damage accumulation, impaired ER-Golgi homeostasis and RINT1 Is Crucial for Retinogenesis autophagy inhibition (Grigaravicius et al, 2016). While these findings reinforced the importance of RINT1 for progenitor cells survival, it remains unclear how and which of the multiple functions of RINT1 contributes to its pleiotropic effects in physiological and pathological contexts. Few studies approached how defects in physiological DDR affects the genesis of retinal neurons (Baranes et al, 2009; Baleriola et al, 2010; Rodrigues et al, 2013; Alvarez-Lindo et al, 2019)
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