Sam68 promotes self-renewal and glycolytic metabolism in mouse neural progenitor cells by modulating Aldh1a3 pre-mRNA 3'-end processing

Elife. 2016 Nov 15;5:e20750. doi: 10.7554/eLife.20750.

Abstract

The balance between self-renewal and differentiation of neural progenitor cells (NPCs) dictates neurogenesis and proper brain development. We found that the RNA- binding protein Sam68 (Khdrbs1) is strongly expressed in neurogenic areas of the neocortex and supports the self-renewing potential of mouse NPCs. Knockout of Khdrbs1 constricted the pool of proliferating NPCs by accelerating their cell cycle exit and differentiation into post-mitotic neurons. Sam68 function was linked to regulation of Aldh1a3 pre-mRNA 3'-end processing. Binding of Sam68 to an intronic polyadenylation site prevents its recognition and premature transcript termination, favoring expression of a functional enzyme. The lower ALDH1A3 expression and activity in Khdrbs1-/- NPCs results in reduced glycolysis and clonogenicity, thus depleting the embryonic NPC pool and limiting cortical expansion. Our study identifies Sam68 as a key regulator of NPC self-renewal and establishes a novel link between modulation of ALDH1A3 expression and maintenance of high glycolytic metabolism in the developing cortex.

Keywords: ALDH1A3; Sam68; alternative splicing; cell biology; glycolytic metabolism; mouse; neural progenitor cells; neuroscience; pre-mRNA processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Gene Knockout Techniques
  • Glycolysis*
  • Mice
  • Neocortex / embryology*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / physiology*
  • Protein Binding
  • RNA Precursors / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Retinal Dehydrogenase / genetics*
  • Stem Cells
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • Khdrbs1 protein, mouse
  • RNA Precursors
  • RNA-Binding Proteins
  • Retinal Dehydrogenase
  • retinaldehyde dehydrogenase 3, mouse

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.