Format

Send to

Choose Destination
Nat Commun. 2017 Mar 20;8:14758. doi: 10.1038/ncomms14758.

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme.

Author information

1
Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
2
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
3
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), CSIC-Universidad de Sevilla-Universidad Pablo de Olavide, Sevilla 41092, Spain.
4
Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
5
Institut Curie, CNRS UMR 3347, INSERM U1021, Centre Universitaire, Bâtiment 110, 91405 Orsay, France.
6
Clinical Cooperation Unit Neuropathology, German Cancer Research Centre (DKFZ), Department of Neuropathology, University of Heidelberg, Heidelberg 69120, Germany.
7
German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany.
8
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
9
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.

Abstract

Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.

PMID:
28317875
PMCID:
PMC5364396
DOI:
10.1038/ncomms14758
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center