Orchestrating Neural Development Through mRNA Translation Regulation

Neural development is a highly intricate process that relies on the precise regulation of gene expression. While a significant focus has been placed on understanding the transcriptional control of brain development, the regulation of mRNA translation plays a fundamental role in controlling gene expression. mRNA translation in subcellular compartments distant from the cell body, such as neuronal growth cones and astrocytic processes, allows for a rapid response to the local environment. Thus, the regulation of mRNA translation influences neurodevelopmental mechanisms such as cell fate decisions, neural stem cell proliferation and differentiation, and axon guidance. As such, the dysregulation of mRNA translation can have profound consequences for neural development, leading to conditions like microcephaly, cortical malformations, autism spectrum disorders, and fragile X syndrome. This review provides an overview of mRNA translation mechanisms that control prenatal brain development and identifies significant knowledge gaps. Specifically, we focus on mRNA translation regulation through signaling cascades such as the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), the integrated stress response, Fragile X Messenger Ribonucleoprotein 1 (FMRP) and eukaryotic elongation factor 2/kinase (eEF2/eEF2K), all of which are critical for mRNA translational regulation and have been previously studied regarding brain development.