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Sci Rep ; 10(1): 18508, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116259

RESUMO

Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. The potent impact of FGF-FGFR in multiple embryonic developmental processes makes it challenging to elucidate their roles in postmitotic neurons. Taking an alternative approach to examine the impact of aberrant FGFR function on glutamatergic neurons, we generated a FGFR gain-of-function (GOF) transgenic mouse, which expresses constitutively activated FGFR3 (FGFR3K650E) in postmitotic glutamatergic neurons. We found that GOF disrupts mitosis of radial-glia neural progenitors (RGCs), inside-out radial migration of post-mitotic glutamatergic neurons, and axonal tract projections. In particular, late-born CUX1-positive neurons are widely dispersed throughout the GOF cortex. Such a cortical migration deficit is likely caused, at least in part, by a significant reduction of the radial processes projecting from RGCs. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our data suggest that FGFR3 GOF in postmitotic neurons not only alters axonal growth of postmitotic neurons but also impairs RGC neurogenesis and radial glia processes.


Assuntos
Axônios/metabolismo , Malformações do Desenvolvimento Cortical/etiologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Aminoácidos Excitatórios/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Mutação com Ganho de Função/genética , Ácido Glutâmico/metabolismo , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Camundongos Transgênicos , Mitose/fisiologia , Neurogênese/fisiologia , Neurônios/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/fisiologia
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