A Translational Repression Complex in Developing Mammalian Neural Stem Cells that Regulates Neuronal Specification

Neuron. 2018 Feb 7;97(3):520-537.e6. doi: 10.1016/j.neuron.2017.12.045. Epub 2018 Jan 27.

Abstract

The mechanisms instructing genesis of neuronal subtypes from mammalian neural precursors are not well understood. To address this issue, we have characterized the transcriptional landscape of radial glial precursors (RPs) in the embryonic murine cortex. We show that individual RPs express mRNA, but not protein, for transcriptional specifiers of both deep and superficial layer cortical neurons. Some of these mRNAs, including the superficial versus deep layer neuron transcriptional regulators Brn1 and Tle4, are translationally repressed by their association with the RNA-binding protein Pumilio2 (Pum2) and the 4E-T protein. Disruption of these repressive complexes in RPs mid-neurogenesis by knocking down 4E-T or Pum2 causes aberrant co-expression of deep layer neuron specification proteins in newborn superficial layer neurons. Thus, cortical RPs are transcriptionally primed to generate diverse types of neurons, and a Pum2/4E-T complex represses translation of some of these neuronal identity mRNAs to ensure appropriate temporal specification of daughter neurons.

Keywords: 4E-T; Pumilio; RNA-binding protein; cortex; development; neural stem cells; neurogenesis; neuronal subtype specification; radial precursors; translational repression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex / embryology*
  • Cerebral Cortex / metabolism
  • Ependymoglial Cells / metabolism*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Gene Expression Regulation, Developmental*
  • Male
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism*
  • Neurogenesis*
  • POU Domain Factors / metabolism
  • Primary Cell Culture
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins / metabolism
  • Sequence Analysis, RNA

Substances

  • Eukaryotic Initiation Factor-4E
  • Nerve Tissue Proteins
  • POU Domain Factors
  • Pum2 protein, mouse
  • RNA, Messenger
  • RNA-Binding Proteins
  • Repressor Proteins
  • Tle4 protein, mouse
  • eIF4E protein, mouse
  • Pou3f3 protein, mouse

Grant support