Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma

Science. 2009 Dec 4;326(5958):1424-7. doi: 10.1126/science.1181453.

Abstract

Granule neuron precursors (GNPs) are the most actively proliferating cells in the postnatal nervous system, and mutations in pathways that control the GNP cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic postnatal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for GNP proliferation, and demonstrate that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. Our data shed light on the function of Atoh1 in postnatal cerebellar development and identify a new mechanism that can be targeted to regulate medulloblastoma formation.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Cerebellar Neoplasms / etiology
  • Cerebellar Neoplasms / prevention & control*
  • Cerebellum / cytology
  • Cerebellum / growth & development
  • Cerebellum / metabolism*
  • Down-Regulation
  • Gene Deletion
  • Gene Knock-In Techniques
  • Hedgehog Proteins / metabolism*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Medulloblastoma / etiology
  • Medulloblastoma / prevention & control*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology
  • Signal Transduction
  • Smoothened Receptor
  • Zinc Finger Protein Gli2

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Gli2 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein Gli2