Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells.
The morphogen and mitogen Sonic Hedgehog (Shh) activates a Gli1-dependent transcription program that drives proliferation of granule neuron progenitors (GNP) within the external germinal layer of the postnatally developing cerebellum. Medulloblastomas with mutations activating the Shh signaling pathway preferentially arise within the external germinal layer, and the tumor cells closely resemble GNPs. Atoh1/Math1, a basic helix-loop-helix transcription factor essential for GNP histogenesis, does not induce medulloblastomas when expressed in primary mouse GNPs that are explanted from the early postnatal cerebellum and transplanted back into the brains of naïve mice. However, enforced expression of Atoh1 in primary GNPs enhances the oncogenicity of cells overexpressing Gli1 by almost three orders of magnitude. Unlike Gli1, Atoh1 cannot support GNP proliferation in the absence of Shh signaling and does not govern expression of canonical cell cycle genes. Instead, Atoh1 maintains GNPs in a Shh-responsive state by regulating genes that trigger neuronal differentiation, including many expressed in response to bone morphogenic protein-4. Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development.
Ayrault
Olivier
O
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Zhao
Haotian
H
Zindy
Frederique
F
Qu
Chunxu
C
Sherr
Charles J
CJ
Roussel
Martine F
MF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1
D051792:Basic Helix-Loop-Helix Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D000071676:Zinc Finger Protein GLI1; C500943:Atoh1 protein, mouse; C493972:Cdkn2c protein, mouse; C498520:Gli1 protein, mouse