Retinoic Acid Is Required for Neural Stem and Progenitor Cell Proliferation in the Adult Hippocampus

Stem Cell Reports. 2018 Jun 5;10(6):1705-1720. doi: 10.1016/j.stemcr.2018.04.024. Epub 2018 May 24.

Abstract

Neural stem and precursor cell (NSPC) proliferation in the rodent adult hippocampus is essential to maintain stem cell populations and produce new neurons. Retinoic acid (RA) signaling is implicated in regulation of adult hippocampal neurogenesis, but its exact role in control of NSPC behavior has not been examined. We show RA signaling in all hippocampal NSPC subtypes and that inhibition of RA synthesis or signaling significantly decreases NSPC proliferation via abrogation of cell-cycle kinetics and cell-cycle regulators. RA signaling controls NSPC proliferation through hypoxia inducible factor-1α (HIF1α), where stabilization of HIF1α concurrent with disruption of RA signaling can prevent NSPC defects. These studies demonstrate a cell-autonomous role for RA signaling in hippocampal NSPCs that substantially broadens RA's function beyond its well-described role in neuronal differentiation.

Keywords: HIF1α; VEGFA; adult neurogenesis; cell cycle; hippocampus; neural stem cells; retinoic acid.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Biomarkers
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Hippocampus / cytology*
  • Hippocampus / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neurogenesis / drug effects
  • Tretinoin / metabolism
  • Tretinoin / pharmacology*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Biomarkers
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A
  • Tretinoin