Translational derepression of Elavl4 isoforms at their alternative 5' UTRs determines neuronal development

Nat Commun. 2020 Apr 3;11(1):1674. doi: 10.1038/s41467-020-15412-8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Alternative Splicing
  • Animals
  • CELF1 Protein / metabolism*
  • Cell Line, Tumor
  • ELAV-Like Protein 4 / genetics*
  • Female
  • Gene Expression Regulation, Developmental*
  • Glutamic Acid / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neocortex / cytology
  • Neocortex / growth & development*
  • Neural Stem Cells / metabolism
  • Neurogenesis / genetics*
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Polyribosomes / metabolism
  • Primary Cell Culture
  • Protein Biosynthesis / genetics
  • RNA Isoforms / genetics
  • RNA-Seq

Substances

  • 5' Untranslated Regions
  • CELF1 Protein
  • CELF1 protein, mouse
  • ELAV-Like Protein 4
  • Elavl4 protein, mouse
  • RNA Isoforms
  • Glutamic Acid