RESUMO
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.
Assuntos
Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação a DNA/metabolismo , Degeneração Neural/patologia , Displasia Retiniana/patologia , Células-Tronco/patologia , Animais , Apoptose , Cegueira/patologia , Morte Celular , Proliferação de Células , Dano ao DNA , Modelos Animais de Doenças , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário , Camundongos , Degeneração Neural/complicações , Neurogênese , Células Fotorreceptoras de Vertebrados/patologia , Retina/patologia , Displasia Retiniana/complicações , Síndrome , Proteína Supressora de Tumor p53/metabolismo , Visão OcularRESUMO
OBJECTIVE: The purpose of this study was to investigate the inheritance and phenotype of retinal dysplasia (RD) in the American pit bull terrier. ANIMALS STUDIED: A breeding colony established from a single female pure-bred American pit bull terrier dog with RD. PROCEDURES: A female pure-bred American pit bull terrier with RD was donated to the Veterinary Hospital of Federal University of Paraná, Curitiba, Brazil. A breeding colony was established and the phenotype and inheritance of the condition investigated. Regular ophthalmic examinations and fundus photography were performed on three generations of offspring from the founder animal. Some animals were additionally studied by optical coherence tomography. Ocular histopathology was performed on some animals from the colony. RESULTS: Fifty-seven offspring were produced in two generations from the affected founder female. Thirty-two were diagnosed with RD and showed a spectrum of severity of lesions including multifocal, and or geographic lesions and some developed retinal detachment. Histologic examination demonstrated retinal folds, rosettes, and areas of retinal detachment. The affected dogs were shorter in stature than the unaffected littermates. Breeding studies suggested the trait has an autosomal dominant mode of inheritance. DNA testing showed that the affected dogs were negative for the known gene mutations for canine dwarfism with RD. CONCLUSION: This is a report of a novel inherited form of RD that affects American pit bull terriers.
Assuntos
Doenças do Cão/patologia , Displasia Retiniana/patologia , Envelhecimento , Animais , Cruzamento , Doenças do Cão/genética , Cães , Feminino , Predisposição Genética para Doença , Masculino , Linhagem , Displasia Retiniana/genéticaRESUMO
Se estudiarion 13 casos de displasia retiniana, entidad poco mencionada en la literatura. Encontramos que todos nuestros casos estuvieron asociados en mayor o menor grado con alteraciones congénitas sistématicas. Se apreció en el estudio histopatológico elementos abortivos de conos y bastones formando rosetas, disminución de las células ganglionares y alteraciones en el epitelio pigmentario. Casi todas las capas retinianas se comprometen en alguna forma, menos las membranas limitante externa e interna.