Genetic activation of Hedgehog signaling unbalances the rate of neural stem cell renewal by increasing symmetric divisions

Stem Cell Reports. 2014 Aug 12;3(2):312-23. doi: 10.1016/j.stemcr.2014.05.016. Epub 2014 Jun 19.

Abstract

In the adult brain, self-renewal is essential for the persistence of neural stem cells (NSCs) throughout life, but its regulation is still poorly understood. One NSC can give birth to two NSCs or one NSC and one transient progenitor. A correct balance is necessary for the maintenance of germinal areas, and understanding the molecular mechanisms underlying NSC division mode is clearly important. Here, we report a function of the Sonic Hedgehog (SHH) receptor Patched in the direct control of long-term NSC self-renewal in the subependymal zone. We show that genetic conditional activation of SHH signaling in adult NSCs leads to their expansion and the depletion of their direct progeny. These phenotypes are associated in vitro with an increase in NSC symmetric division in a process involving NOTCH signaling. Together, our results demonstrate a tight control of adult neurogenesis and NSC renewal driven by Patched.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System X-AG / genetics
  • Animals
  • Brain / metabolism
  • Cell Proliferation / drug effects
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Neurogenesis
  • Patched Receptors
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Notch / metabolism
  • Selective Estrogen Receptor Modulators / pharmacology
  • Signal Transduction
  • Tamoxifen / pharmacology
  • Up-Regulation
  • Zinc Finger Protein GLI1

Substances

  • Amino Acid Transport System X-AG
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Patched Receptors
  • Receptors, Cell Surface
  • Receptors, Notch
  • Selective Estrogen Receptor Modulators
  • Zinc Finger Protein GLI1
  • Tamoxifen