A Transcriptional Mechanism Integrating Inputs From Extracellular Signals to Activate Hippocampal Stem Cells

Neuron. 2014 Sep 3;83(5):1085-97. doi: 10.1016/j.neuron.2014.08.004.

Abstract

The activity of adult stem cells is regulated by signals emanating from the surrounding tissue. Many niche signals have been identified, but it is unclear how they influence the choice of stem cells to remain quiescent or divide. Here we show that when stem cells of the adult hippocampus receive activating signals, they first induce the expression of the transcription factor Ascl1 and only subsequently exit quiescence. Moreover, lowering Ascl1 expression reduces the proliferation rate of hippocampal stem cells, and inactivating Ascl1 blocks quiescence exit completely, rendering them unresponsive to activating stimuli. Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating the expression of cell-cycle regulatory genes. Ascl1 is similarly required for stem cell activation in the adult subventricular zone. Our results support a model whereby Ascl1 integrates inputs from both stimulatory and inhibitory signals and converts them into a transcriptional program activating adult neural stem cells.

Publication types

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

MeSH terms

  • Adult Stem Cells / cytology*
  • Adult Stem Cells / metabolism
  • Age Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Proliferation
  • Cerebral Ventricles / cytology
  • Excitatory Amino Acid Transporter 1 / genetics
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / cytology*
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / deficiency
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Kainic Acid / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurogenesis / genetics*
  • T-Box Domain Proteins / metabolism
  • p300-CBP Transcription Factors / metabolism

Substances

  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Eomes protein, mouse
  • Excitatory Amino Acid Transporter 1
  • Glial Fibrillary Acidic Protein
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Slc1a3 protein, mouse
  • T-Box Domain Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse
  • p300-CBP Transcription Factors
  • Kainic Acid