Stox1 as a novel transcriptional suppressor of Math1 during cerebellar granule neurogenesis and medulloblastoma formation

Cell Death Differ. 2016 Dec;23(12):2042-2053. doi: 10.1038/cdd.2016.85. Epub 2016 Aug 26.

Abstract

Cerebellar granule neuronal progenitors (GNPs) are the precursors of cerebellar granule cells (CGCs) and are believed to be the cell of origin for medulloblastoma (MB), yet the molecular mechanisms governing GNP neurogenesis are poorly elucidated. Here, we demonstrate that storkhead box 1 (Stox1), a forkhead transcriptional factor, has a pivotal role in cerebellar granule neurogenesis and MB suppression. Expression of Stox1 is upregulated along with GNP differentiation and repressed by activation of sonic hedgehog (SHH) signaling. Stox1 exerts its neurogenic and oncosuppressing effect via direct transcriptional repression of Math1, a basic helix-loop-helix transcription activator essential for CGC genesis. This study illustrates a SHH-Stox1-Math1 regulatory axis in normal cerebellar development and MB formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carrier Proteins / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cerebellar Neoplasms / genetics*
  • Cerebellar Neoplasms / pathology
  • Cerebellum / growth & development
  • Cerebellum / metabolism*
  • Cytoplasmic Granules / metabolism*
  • Gene Knockdown Techniques
  • Hedgehog Proteins
  • Medulloblastoma / genetics*
  • Medulloblastoma / pathology
  • Mice
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis*
  • Patched Receptors / deficiency
  • Patched Receptors / metabolism
  • Signal Transduction
  • Transcription, Genetic*

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Carrier Proteins
  • Hedgehog Proteins
  • Patched Receptors
  • STOX1 protein, mouse
  • Shh protein, mouse