Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans

Cell Rep. 2015 Feb 24;10(7):1158-72. doi: 10.1016/j.celrep.2015.01.049. Epub 2015 Feb 19.

Abstract

Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism*
  • Neurogenesis / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Vascular Endothelial Growth Factor C / genetics
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor C / pharmacology
  • Vascular Endothelial Growth Factor Receptor-3 / genetics
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism*

Substances

  • Recombinant Proteins
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases