RESUMO
The nuclei of progenitor cells in developing neural epithelia change their position during the cell cycle through a process called interkinetic nuclear migration. Del Bene et al. (2008) report that defects in the machinery controlling this process lead to altered exposure to Notch signals and systemic effects on neurogenesis in the retina.
Assuntos
Núcleo Celular/metabolismo , Receptores Notch/metabolismo , Retina/embriologia , Animais , Células Neuroepiteliais/citologia , Retina/citologia , Retina/metabolismo , Células-Tronco/citologia , Peixe-ZebraRESUMO
Autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder in which patients display significantly reduced brain size. Mutations in Abnormal Spindle Microcephaly (ASPM) are the most common cause of MCPH. Here, we investigate the underlying functions of Aspm in brain development and find that Aspm expression is critical for proper neurogenesis and neuronal migration. The Wnt signaling pathway is known for its roles in embryogenesis, and genome-wide siRNA screens indicate that ASPM is a positive regulator of Wnt signaling. We demonstrate that knockdown of Aspm results in decreased Wnt-mediated transcription, and that expression of stabilized ß-catenin can rescue this deficit. Finally, coexpression of stabilized ß-catenin can rescue defects observed upon in vivo knockdown of Aspm. Our findings provide an impetus to further explore Aspm's role in facilitating Wnt-mediated neurogenesis programs, which may contribute to psychiatric illness etiology when perturbed.
Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Animais , Proteínas de Ligação a Calmodulina , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Técnicas de Silenciamento de Genes , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Células-Tronco/citologia , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Centrosome- and microtubule-associated proteins have been shown to be important for maintaining the neural progenitor pool during neocortical development by regulating the mitotic spindle. It remains unclear whether these proteins may control neurogenesis by regulating other microtubule-dependent processes such as nuclear migration. Here, we identify Cep120, a centrosomal protein preferentially expressed in neural progenitors during neocortical development. We demonstrate that silencing Cep120 in the developing neocortex impairs both interkinetic nuclear migration (INM), a characteristic pattern of nuclear movement in neural progenitors, and neural progenitor self-renewal. Furthermore, we show that Cep120 interacts with transforming acidic coiled-coil proteins (TACCs) and that silencing TACCs also causes defects in INM and neural progenitor self-renewal. Our data suggest a critical role for Cep120 and TACCs in both INM and neurogenesis. We propose that sustaining INM may be a mechanism by which microtubule-regulating proteins maintain the neural progenitor pool during neocortical development.
Assuntos
Proteínas de Ciclo Celular/fisiologia , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Neurônios/fisiologia , Células-Tronco/citologia , Células-Tronco/fisiologia , Animais , Proteínas de Ciclo Celular/genética , Núcleo Celular/metabolismo , Eletroporação/métodos , Embrião de Mamíferos , Feminino , Técnicas In Vitro , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neocórtex/citologia , Neocórtex/embriologia , Neocórtex/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Gravidez , Transporte Proteico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fatores de Tempo , Transfecção/métodosRESUMO
Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.
Assuntos
Antígenos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neocórtex/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Análise de Variância , Animais , Antígenos/genética , Western Blotting , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Células Cultivadas , Centrossomo/metabolismo , Imunofluorescência , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Espectrometria de Massas , Camundongos , Microscopia Confocal , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Domínios e Motivos de Interação entre Proteínas/genética , Transporte Proteico/genética , Interferência de RNARESUMO
The mitotic spindle is the cellular scaffold that facilitates proper segregation of genetic material during cell division. Far from being static, the spindle is a dynamically regulated tool that can alter its size, shape and position during mitosis. Work in both insect and vertebrate systems has shown that regulation of this structure involves an array of highly conserved proteins. Moreover, it is now clear that tight regulation of the spindle during the process of neurogenesis is paramount to proper cell division and generation of the nervous system as a whole.