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Inducible and Reversible Dominant-negative DN Protein Inhibition
Published on: January 7, 2019
RINT1 Loss Impairs Retinogenesis Through TRP53-Mediated Apoptosis
Anielle L Gomes1, Gabriel E Matos-Rodrigues1, Pierre-Olivier Frappart2
1Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
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.
Insights
Loss of Rad50-interacting protein 1 (RINT1) in developing retinal cells causes DNA damage and blindness. Trp53-mediated apoptosis prevents visual system malformations, highlighting its role in DNA damage response.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Genomic instability in the central nervous system (CNS) is linked to neurodevelopmental and neurodegenerative disorders.
- Mutations in DNA damage response (DDR) genes cause congenital CNS developmental syndromes.
- Rad50-interacting protein 1 (RINT1) is crucial for DNA double-strand break repair and embryonic brain cell survival.
Purpose of the Study:
- To investigate the role of RINT1 in CNS development by conditionally inactivating it in retinal progenitor cells (RPCs).
- To understand the consequences of RINT1 loss on neurogenesis and visual system development, bypassing embryonic lethality.
Main Methods:
- Conditional inactivation of the RINT1 gene in RPCs during mouse embryogenesis.
- Analysis of DNA damage accumulation, cell cycle checkpoint activation, apoptosis, and neurogenesis.
- Assessment of optic nerve development and visual function.
- Inactivation of the Trp53 gene to evaluate its role in RINT1-deficient RPCs.
Main Results:
- RINT1 loss in RPCs led to endogenous DNA damage but did not impair cell cycle checkpoint activation.
- RINT1 deficiency caused apoptosis of proliferating progenitors and postmitotic neurons, resulting in failed retinal neurogenesis.
- Optic nerve malformation and blindness were observed in RINT1-deficient mice.
- Trp53 inactivation rescued RPC apoptosis and restored retinal neuron generation and vision.
Conclusions:
- RINT1 is essential for maintaining genomic stability and normal neurogenesis in the developing retina.
- TRP53-mediated apoptosis plays a critical role in preventing visual system malformations following RINT1 loss.
- Defective DNA damage response pathways contribute to retinal malformations and vision loss.
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