Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma.
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.
Flora
Adriano
A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Klisch
Tiemo J
TJ
Schuster
Gabriele
G
Zoghbi
Huda Y
HY
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000502:physiology*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000209:etiology / Q000517:prevention & control*; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D015536:Down-Regulation; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2
D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2; C500943:Atoh1 protein, mouse; C000618551:Gli2 protein, mouse; C465570:Shh protein, mouse; C491022:Smo protein, mouse