RESUMO
Presenilin-1 (PS1) is a transmembrane protein that is in many cases responsible for the development of familial Alzheimer's disease. PS1 is widely expressed in embryogenesis and is essential for neurogenesis, somitogenesis, angiogenesis, and cardiac morphogenesis. To further investigate the role of PS1 in the brain, we inactivated the PS1 gene in Wnt1 cell lineages using the Cre-loxP recombination system. Here we show that conditional inactivation of PS1 in Wnt1 cell lineages results in congenital hydrocephalus and subcommissural organ abnormalities, suggesting a possible role of PS1 in the regulation of cerebrospinal fluid homeostasis.
Assuntos
Predisposição Genética para Doença/genética , Hidrocefalia/genética , Malformações do Sistema Nervoso/genética , Presenilina-1/genética , Órgão Subcomissural/anormalidades , Proteína Wnt1/genética , Animais , Linhagem da Célula/genética , Ventrículos Cerebrais/anormalidades , Ventrículos Cerebrais/patologia , Líquido Cefalorraquidiano/fisiologia , Pressão do Líquido Cefalorraquidiano/fisiologia , Modelos Animais de Doenças , Homeostase/genética , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/patologia , Presenilina-1/antagonistas & inibidores , Presenilina-1/deficiência , Órgão Subcomissural/fisiopatologiaRESUMO
Huntingtin (htt) is a 350 kDa protein of unknown function, with no homologies with other known proteins. Expansion of a polyglutamine stretch at the N-terminus of htt causes Huntington's disease (HD), a dominant neurodegenerative disorder. Although it is generally accepted that HD is caused primarily by a gain-of-function mechanism, recent studies suggest that loss-of-function may also be part of HD pathogenesis. Huntingtin is an essential protein in the mouse since inactivation of the mouse HD homolog (Hdh) gene results in early embryonic lethality. Huntingtin is widely expressed in embryogenesis, and associated with a number of interacting proteins suggesting that htt may be involved in several processes including morphogenesis, neurogenesis and neuronal survival. To further investigate the role of htt in these processes, we have inactivated the Hdh gene in Wnt1 cell lineages using the Cre-loxP system of recombination. Here we show that conditional inactivation of the Hdh gene in Wnt1 cell lineages results in congenital hydrocephalus, implicating huntingtin for the first time in the regulation of cerebral spinal fluid (CSF) homeostasis. Our results show that hydrocephalus in mice lacking htt in Wnt1 cell lineages is associated with increase in CSF production by the choroid plexus, and abnormal subcommissural organ.
Assuntos
Linhagem da Célula , Hidrocefalia/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Órgão Subcomissural/anormalidades , Proteína Wnt1/metabolismo , Animais , Plexo Corióideo/anormalidades , Plexo Corióideo/embriologia , Plexo Corióideo/metabolismo , Feminino , Inativação Gênica , Humanos , Proteína Huntingtina , Hidrocefalia/embriologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Órgão Subcomissural/embriologia , Órgão Subcomissural/metabolismo , Proteína Wnt1/genéticaRESUMO
A single whole-body X-irradiation of pregnant Wistar rats at a dose of 1.05 Gy at 10.30, 12.30 and 14.30 h respectively, of gestational day 10 resulted in significantly high incidences of hydrocephalic offspring. No hydrocephalic offspring resulted from X-irradiation of pregnant rats with 1.05 Gy at 16.30 h, whereas a dose of 1.22 Gy at 16.30 h resulted in a low but statistically significant incidence of hydrocephalus. Neither 1.05 Gy nor 1.22 Gy X-irradiation of pregnant rats at 18.30 h resulted in any hydrocephalic offspring. Dysplasia of the subcommissural organ was noticed in all the hydrocephalic brains histologically examined.