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
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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