RESUMO
The regulated proliferation and differentiation of neural stem cells before the generation and migration of neurons in the cerebral cortex are central aspects of mammalian development. Periventricular neuronal heterotopia, a specific form of mislocalization of cortical neurons, can arise from neuronal progenitors that fail to negotiate aspects of these developmental processes. Here we show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia. Reducing the expression of Dchs1 or Fat4 within mouse embryonic neuroepithelium increased progenitor cell numbers and reduced their differentiation into neurons, resulting in the heterotopic accumulation of cells below the neuronal layers in the neocortex, reminiscent of the human phenotype. These effects were countered by concurrent knockdown of Yap, a transcriptional effector of the Hippo signaling pathway. These findings implicate Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.
Assuntos
Caderinas/genética , Córtex Cerebral/embriologia , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Proteínas Supressoras de Tumor/genética , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sequência de Bases , Proteínas Relacionadas a Caderinas , Proteínas de Ciclo Celular , Diferenciação Celular , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Anormalidades Craniofaciais/genética , Deformidades Congênitas do Pé/genética , Técnicas de Silenciamento de Genes , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/genética , Instabilidade Articular/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Heterotopia Nodular Periventricular/genética , Fosfoproteínas/genética , Análise de Sequência de DNA , Transdução de Sinais/genética , Proteínas de Sinalização YAPRESUMO
OBJECTIVE: To report the prenatal findings and postnatal outcome of fetal ventriculomegaly associated with isolated large choroid plexus cysts (CPCs). METHOD: Cases of isolated fetal ventriculomegaly and large CPCs (>10 mm) were identified through a search of patient records from 2003 to 2006. Ultrasound (US) findings were reviewed: unilateral or bilateral ventriculomegaly, ventricular size, size of CPCs, and changes on serial scans. Correlation was made with fetal magnetic resonance imaging (MRI), pregnancy outcome, and long-term follow-up. RESULTS: Six cases of isolated large CPCs (12-30 mm) with ventriculomegaly (11-17 mm) were detected on US at 18 to 26 weeks of gestation. Serial prenatal US showed the CPCs resolved (one case) or decreased in size (five cases). Ventricular size became normal during pregnancy in five cases and decreased in size in one case. Fetal MRI performed in three cases showed no additional findings. Five patients had amniocentesis which showed normal karyotype. There was one termination of pregnancy (the fetus showed no abnormality on external examination). There were five healthy newborns, with follow-up to 4.5 years of age (one), 5.5 years (one), and 6 years (three). All had normal physical and developmental outcome. CONCLUSION: Large isolated CPCs may transiently dilate the fetal cerebral ventricles. Follow-up to 6 years has shown normal growth and development.