RESUMO
Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first 2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1A gene (SET domain-containing 1A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations (R913C, Q269R, G1369R, and R1392H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913C mutation also affected the migration of cortical neurons in the mouse brain. We further identified two common genes (Neurl4 and Usp39) affected by mutations of SETD1A. These results suggested that the mutations of SETD1A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.
Assuntos
Epilepsia/genética , Histona-Lisina N-Metiltransferase/genética , Animais , Epilepsia/metabolismo , Epilepsia/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Cultura Primária de Células , Convulsões/etiologia , Convulsões/genética , Convulsões/metabolismo , Convulsões/patologia , Ubiquitina-Proteína Ligases/metabolismo , Proteases Específicas de Ubiquitina/metabolismoAssuntos
Encéfalo/crescimento & desenvolvimento , Deficiência Intelectual/genética , Proteína Proto-Oncogênica N-Myc/genética , Animais , Criança , Pálpebras/anormalidades , Feminino , Humanos , Deformidades Congênitas dos Membros/genética , Camundongos , Microcefalia/genética , Mutação de Sentido Incorreto , Fístula Traqueoesofágica/genéticaRESUMO
Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice. Interestingly, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 TG mice, which were critical for determining fates of adult hippocampal NSCs between the quiescence and activation. In summary, we found that MeCP2 plays a critical role in regulating fate determination of adult NSCs. These evidences further suggest that abnormal development of NSCs may play a role in the pathogenesis of the MECP2 duplication syndrome.
Assuntos
Hipocampo/citologia , Hipocampo/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Células-Tronco Neurais/fisiologia , Fase de Repouso do Ciclo Celular , Animais , Diferenciação Celular , Proliferação de Células , Giro Denteado , Modelos Animais de Doenças , Expressão Gênica , Interneurônios/citologia , Interneurônios/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Camundongos , Camundongos Transgênicos , Células-Tronco Neurais/citologia , NeurogêneseRESUMO
BACKGROUND: The tumor suppressor gene Phosphatase and tensin homolog (PTEN) is highly expressed in neural progenitor cells (NPCs) and plays an important role in development of the central nervous system. As a dual-specificity phosphatase, the loss of PTEN phosphatase activity has been linked to various diseases. RESULTS: Here we report that the protein phosphatase activity of Pten is critical for regulating differentiation of neural progenitor cells. First we found that deletion of Pten promotes neuronal differentiation. To determine whether the protein or lipid phosphatase activity is required for regulating neuronal differentiation, we generated phosphatase domain-specific Pten mutations. Interestingly, only expression of protein phosphatase-deficient mutant Y138L could mimic the effect of knocking down Pten, suggesting the protein phosphatase of Pten is critical for regulating NPC differentiation. Importantly, we showed that the wild-type and lipid phosphatase mutant (G129E) forms of Pten are able to rescue neuronal differentiation in Pten knockout NPCs, but mutants containing protein phosphatase mutant cannot. We further found that Pten-dependent dephosphorylation of CREB is critical for neuronal differentiation. CONCLUSION: Our data indicate that the protein phosphatase activity of PTEN is critical for regulating differentiation of NSCs during cortical development.