RESUMO
Neuronal migration and morphogenesis are fundamental processes for cortical development. Their defects may cause abnormities in neural circuit formation and even neuropsychiatric disorders. Many proteins, especially layer-specific transcription factors and adhesion molecules, have been reported to regulate the processes. However, the involvement of non-coding RNAs in cortical development has not been extensively studied. Here, we identified microRNA-218 (miR-218) as a layer V-specific microRNA in mouse brains. Expression of miR-218 was elevated in patients with autism spectrum disorder (ASD) and schizophrenia. We found in this study that miR-218 overexpression in developing mouse cortex led to severe defects in radial migration, morphogenesis, and spatial distribution of the cortical neurons. Moreover, we identified Satb2, an upper-layer marker, as a molecular target repressed by miR-218. These results suggest an underlying mechanism of miR-218 involvement in neuropsychiatric disorders, and the interactions of layer-specific non-coding RNAs and proteins in regulating cortical development.
Assuntos
Transtorno do Espectro Autista , Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , Neocórtex , Fatores de Transcrição , Animais , Camundongos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Movimento Celular/genética , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neocórtex/metabolismo , Neurogênese/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , HumanosRESUMO
The human cerebral neocortex is divided into six layers consisting of specific neuronal cell types and connections. To determine the distribution of cortical neurons during early development, we examined the expressions of layer-specific markers in human midterm fetal brains. Layer V marker ZNF312 is expressed in most cortical areas, but not in the prospective somatosensory association area. Expression of layer IV marker RORbeta is also diminished in this region but increased in the primary visual cortex, where expression of ZNF312 is reduced. Our results indicate that ZNF312 and other layer markers have area dependent expressions in the human fetal cortex.