Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of Atrip-Seckel syndrome
Autor: | Rodrigo A. P. Martins, Anielle L. Gomes, Paulius Grigaravicius, Pedro B. Tan, Pierre Olivier Frappart, Gabriel E. Matos-Rodrigues, Clara Forrer Charlier, Felipe Cabral-Miranda, Thomas G. Hofmann, Mauricio Rocha-Martins |
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Rok vydání: | 2020 |
Předmět: |
lcsh:Medicine
Medicine (miscellaneous) Blindness Mice chemistry.chemical_compound Immunology and Microbiology (miscellaneous) Cell Death neurodevelopment Stem Cells Neurodegeneration apoptosis neurodegeneration Syndrome Cell biology DNA-Binding Proteins dna damage response medicine.anatomical_structure Photoreceptor Cells Vertebrate Research Article lcsh:RB1-214 Neurogenesis Neuroscience (miscellaneous) Embryonic Development Biology Retina General Biochemistry Genetics and Molecular Biology lcsh:Pathology medicine Animals Abnormalities Multiple Progenitor cell Vision Ocular Adaptor Proteins Signal Transducing Cell Proliferation Progenitor lcsh:R Retinal Embryo Mammalian medicine.disease photoreceptor Disease Models Animal Seckel syndrome chemistry visual system development Nerve Degeneration Retinal dysplasia Retinal Dysplasia Tumor Suppressor Protein p53 Primordial dwarfism DNA Damage |
Zdroj: | Disease Models & Mechanisms, Vol 13, Iss 10 (2020) Disease Models & Mechanisms article-version (VoR) Version of Record |
ISSN: | 1754-8411 1754-8403 |
Popis: | 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 and 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 investigated the cellular and molecular consequences of ATRIP deficiency in different cell populations of the developing murine neural retina. We discovered that conditional inactivation of Atrip in photoreceptor neurons did not affect their survival or function. In contrast, Atrip deficiency in retinal progenitor cells (RPCs) led to severe lamination defects followed by secondary photoreceptor degeneration and loss of vision. Furthermore, we showed that RPCs lacking functional ATRIP exhibited higher levels of replicative stress and accumulated endogenous DNA damage that was accompanied by stabilization of TRP53. Notably, inactivation of Trp53 prevented apoptosis of Atrip-deficient progenitor cells and was sufficient to rescue retinal dysplasia, neurodegeneration and loss of vision. 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 might contribute to retinal malformations in Seckel syndrome and other MPD disorders. This article has an associated First Person interview with the first author of the paper. Summary: Retinopathies have been reported in primordial dwarfism syndromes. We show that the loss of Atrip, a gene mutated in Seckel syndrome, causes photoreceptor degeneration owing to p53-dependent apoptosis of retinal progenitors during development. |
Databáze: | OpenAIRE |
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