RESUMO
Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size.
Assuntos
Encéfalo/embriologia , Encéfalo/metabolismo , Proliferação de Células , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição Forkhead/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Neurogênese/fisiologia , Células-Tronco/citologia , Fatores de Transcrição/fisiologia , Sequência de Aminoácidos , Animais , Ciclo Celular , Diferenciação Celular , Células Cultivadas , Imunoprecipitação da Cromatina , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Imunofluorescência , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy associated with deletions of a subtelomeric repeat (D4Z4). A reduction in D4Z4 copy number coincides with increased expression of neighboring 4q35 genes, implying a normal repressive role for the repeats. Here we examine the effect of increasing D4Z4 repeat number on reporter gene activity in C2C12 cells. Repeat size had only a minor cis-effect on reporter gene activity but greatly compromised myotube formation. This latter trans-effect did not result from expression of a gene within the repeat (DUX4) but likely results from squelching of the D4Z4 recognition complex.
