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Dev Cell. 2014 Jun 23;29(6):649-61. doi: 10.1016/j.devcel.2014.05.014.

Shh signaling protects Atoh1 from degradation mediated by the E3 ubiquitin ligase Huwe1 in neural precursors.

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Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
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.
In Vivo Experiments Facility, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
Institut Curie, CNRS UMR 3306, INSERM U1005, Centre Universitaire, Bâtiment 110, 91405 Orsay, France. Electronic address:


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.

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