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Dev Cell. 2019 Jan 28;48(2):184-199.e5. doi: 10.1016/j.devcel.2018.12.017.

Atoh1 Controls Primary Cilia Formation to Allow for SHH-Triggered Granule Neuron Progenitor Proliferation.

Author information

1
Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan.
2
Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay 91405, France; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay 91405, France.
3
Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
4
Department of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
5
Institute of Biochemistry and Molecular Biology, College of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan.
6
CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, Gif-sur-Yvette, Paris 91198, France.
7
Ecole Normale Supérieure, Institut de Biologie de l'ENS, IBENS, Paris 75005, France; CNRS, UMR8197, Paris 75005, France; INSERM, U1024, Paris 75005, France.
8
Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan; Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: tsaijw@ym.edu.tw.
9
Institut Curie, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay 91405, France; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay 91405, France. Electronic address: olivier.ayrault@curie.fr.

Abstract

During cerebellar development, granule neuron progenitors (GNPs) proliferate by transducing Sonic Hedgehog (SHH) signaling via the primary cilium. Precise regulation of ciliogenesis, thus, ensures proper GNP pool expansion. Here, we report that Atoh1, a transcription factor required for GNPs formation, controls the presence of primary cilia, maintaining GNPs responsiveness to SHH. Loss of primary cilia abolishes the ability of Atoh1 to keep GNPs in a proliferative state. Mechanistically, Atoh1 promotes ciliogenesis by transcriptionally regulating Cep131, which facilitates centriolar satellite (CS) clustering to the basal body. Importantly, ectopic expression of Cep131 counteracts the effects of Atoh1 loss in GNPs by restoring proper localization of CS and ciliogenesis. This Atoh1-CS-primary cilium-SHH pro-proliferative pathway is also conserved in SHH-type medulloblastoma, a pediatric brain tumor arising from the GNPs. Together, our data reveal how Atoh1 modulates the primary cilium to regulate GNPs development.

KEYWORDS:

Atoh1 (Math1); Cep131 (Azi1); Pcm1; centriolar satellites; cerebellar development; granule neuron progenitors; medulloblastoma; primary cilium; sonic hedgehog

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