RESUMO
Neurodevelopment requires precise regulation of gene expression, including post-transcriptional regulatory events such as alternative splicing and mRNA translation. However, translational regulation of specific isoforms during neurodevelopment and the mechanisms behind it remain unknown. Using RNA-seq analysis of mouse neocortical polysomes, here we report translationally repressed and derepressed mRNA isoforms during neocortical neurogenesis whose orthologs include risk genes for neurodevelopmental disorders. We demonstrate that the translation of distinct mRNA isoforms of the RNA binding protein (RBP), Elavl4, in radial glia progenitors and early neurons depends on its alternative 5' UTRs. Furthermore, 5' UTR-driven Elavl4 isoform-specific translation depends on upstream control by another RBP, Celf1. Celf1 regulation of Elavl4 translation dictates development of glutamatergic neurons. Our findings reveal a dynamic interplay between distinct RBPs and alternative 5' UTRs in neuronal development and underscore the risk of post-transcriptional dysregulation in co-occurring neurodevelopmental disorders.
Assuntos
Proteínas CELF1/metabolismo , Proteína Semelhante a ELAV 4/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/crescimento & desenvolvimento , Neurogênese/genética , Regiões 5' não Traduzidas/genética , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neocórtex/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Polirribossomos/metabolismo , Cultura Primária de Células , Biossíntese de Proteínas/genética , Isoformas de RNA/genética , RNA-SeqRESUMO
More than a passive effector of gene expression, mRNA translation (protein synthesis) by the ribosome is a rapidly tunable and dynamic molecular mechanism. Neurodevelopmental disorders are associated with abnormalities in mRNA translation, protein synthesis, and neocortical development; yet, we know little about the molecular mechanisms underlying these abnormalities. Furthermore, our understanding of regulation of the ribosome and mRNA translation during normal brain development is only in its early stages. mRNA translation is emerging as a key driver of the rapid and timed regulation of spatiotemporal gene expression in the developing nervous system, including the neocortex. In this review, we focus on the regulatory role of the ribosome in neocortical development, and construct a current understanding of how ribosomal complex specificity may contribute to the development of the neocortex. We also present a microarray analysis of ribosomal protein-coding mRNAs across the neurogenic phase of neocortical development, in addition to the dynamic enrichment of these mRNAs in actively translating neocortical polysomal ribosomes. Understanding the multivariate control of mRNA translation by ribosomal complex specificity will be critical to reveal the intricate mechanisms of normal brain development and pathologies of neurodevelopmental disorders.