The Orphan Nuclear Receptor TLX Represses Hes1 Expression, Thereby Affecting NOTCH Signaling and Lineage Progression in the Adult SEZ

Stem Cell Reports. 2019 Jul 9;13(1):132-146. doi: 10.1016/j.stemcr.2019.05.004. Epub 2019 Jun 6.

Abstract

In the adult subependymal zone (SEZ), neural stem cells (NSCs) apically contacting the lateral ventricle on activation generate progenitors proliferating at the niche basal side. We here show that Tailless (TLX) coordinates NSC activation and basal progenitor proliferation by repressing the NOTCH effector Hes1. Consistent with this, besides quiescence Hes1 expression also increases on Tlx mutation. Since HES1 levels are higher at the apical SEZ, NOTCH activation is increased in Tlx-/- NSCs, but not in surrounding basal progenitors. Underscoring the causative relationship between higher HES1/NOTCH and increased quiescence, downregulation of Hes1 only in mutant NSCs normalizes NOTCH activation and resumes proliferation and neurogenesis not only in NSCs, but especially in basal progenitors. Since pharmacological blockade of NOTCH signaling also promotes proliferation of basal progenitors, we conclude that TLX, by repressing Hes1 expression, counteracts quiescence and NOTCH activation in NSCs, thereby relieving NOTCH-mediated lateral inhibition of proliferation in basal progenitors.

Keywords: Hes1; Mash1; NOTCH signaling; Tlx; neural stem cells; neurogenesis; quiescence; subependymal zone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cell Proliferation
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Lateral Ventricles / cytology
  • Lateral Ventricles / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Transcription Factor HES-1 / genetics*

Substances

  • Hes1 protein, mouse
  • Nr2e1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Notch
  • Transcription Factor HES-1