title: Shh signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors.
abstract: Signaling networks controlled by Sonic hedgehog (SHH) and the transcription factor Atoh1 regulate the proliferation and differentiation of cerebellar granule neuron progenitors (GNPs). Deregulations in those developmental processes lead to medulloblastoma formation, the most common malignant brain tumor in childhood. Although the protein Atoh1 is a key factor during both cerebellar development and medulloblastoma formation, up-to-date detailed mechanisms underlying its function and regulation have remained poorly understood. Here, we report that SHH regulates Atoh1 stability by preventing its phosphodependent degradation by the E3 ubiquitin ligase Huwe1. Our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 loss in mouse SHH medulloblastoma illustrates the disruption of this developmental mechanism in cancer. Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Antoine
authors: A
authors: Forget
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Laure
authors: L
authors: Bihannic
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Sara Maria
authors: SM
authors: Cigna
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Coralie
authors: C
authors: Lefevre
authors: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Marc
authors: M
authors: Remke
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Monia
authors: M
authors: Barnat
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Sophie
authors: S
authors: Dodier
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Hamasseh
authors: H
authors: Shirvani
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Audrey
authors: A
authors: Mercier
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Aurore
authors: A
authors: Mensah
authors: In Vivo Experiments Facility, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors: Mickael
authors: M
authors: Garcia
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
authors: Sandrine
authors: S
authors: Humbert
authors: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Michael D
authors: MD
authors: Taylor
authors: Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
authors: Anna
authors: A
authors: Lasorella
authors: Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France. Electronic address: olivier.ayrault@curie.fr.
authors: Olivier
authors: O
authors: Ayrault
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002846:Chromatography, Affinity; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D000072079:Patched Receptors; D010766:Phosphorylation; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015996:Survival Rate; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism* / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; C500943:Atoh1 protein, mouse; C465570:Shh protein, mouse; C502830:HUWE1 protein, human; C502831:Huwe1 protein, mouse