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Nat Neurosci. 2016 Aug;19(8):1060-72. doi: 10.1038/nn.4322. Epub 2016 Jun 13.

Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination.

Author information

1
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
2
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
3
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, the Netherlands.
4
Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
5
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
6
Department of Biological Science, Rutgers University, Newark, New Jersey, USA.
7
VIB Center for the Biology of Disease, KU Leuven Department of Human Genetics, Leuven, Belgium.
8
Department of Neurology, Program in Biomedical and Neurosciences, University of California, San Francisco, San Francisco, California, USA.
9
Laboratory of Molecular Biology (Celgen), KU Leuven Department of Development and Regeneration, Leuven, Belgium.
10
Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.

Abstract

The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box-binding homeobox 2 (Zeb2, also called Sip1) transcription factor is a critical intrinsic timer that controls the onset of SC differentiation by recruiting histone deacetylases HDAC 1 and 2 (HDAC1/2) and nucleosome remodeling and deacetylase complex (NuRD) co-repressor complexes in mice. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene encoding the Notch effector Hey2 as a potent inhibitor for Schwann cell differentiation. Strikingly, a genetic Zeb2 variant associated with Mowat-Wilson syndrome disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

PMID:
27294509
PMCID:
PMC4961522
DOI:
10.1038/nn.4322
[Indexed for MEDLINE]
Free PMC Article

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