Zeb2 Recruits HDAC-NuRD to Inhibit Notch and Controls Schwann Cell Differentiation and Remyelination

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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/Sip1) transcription factor is a critical intrinsic timer that controls the onset of Schwann cell (SC) differentiation by recruiting HDAC1/2-NuRD co-repressor complexes. 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 SC differentiation. Strikingly, a genetic Zeb2 variant, which is 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 novel Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

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Most cited references 44

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The origin and development of glial cells in peripheral nerves.

Kristjan Jessen, Rhona Mirsky (2005)

During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating glial cells in a process that parallels gliogenesis from the germinal layers of the CNS. Unlike central gliogenesis, neural crest development involves a protracted embryonic phase devoted to the generation of, first, the Schwann cell precursor and then the immature Schwann cell, a cell whose fate as a myelinating or non-myelinating cell has yet to be determined. Embryonic nerves therefore offer a particular opportunity to analyse the early steps of gliogenesis from transient multipotent stem cells, and to understand how this process is integrated with organogenesis of peripheral nerves.

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Myelination of the nervous system: mechanisms and functions.

Klaus-Armin Nave, Hauke B. Werner (2014)

Myelination of axons in the nervous system of vertebrates enables fast, saltatory impulse propagation, one of the best-understood concepts in neurophysiology. However, it took a long while to recognize the mechanistic complexity both of myelination by oligodendrocytes and Schwann cells and of their cellular interactions. In this review, we highlight recent advances in our understanding of myelin biogenesis, its lifelong plasticity, and the reciprocal interactions of myelinating glia with the axons they ensheath. In the central nervous system, myelination is also stimulated by axonal activity and astrocytes, whereas myelin clearance involves microglia/macrophages. Once myelinated, the long-term integrity of axons depends on glial supply of metabolites and neurotrophic factors. The relevance of this axoglial symbiosis is illustrated in normal brain aging and human myelin diseases, which can be studied in corresponding mouse models. Thus, myelinating cells serve a key role in preserving the connectivity and functions of a healthy nervous system.

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Krox-20 controls myelination in the peripheral nervous system.

S. Schneider, P Charnay, T Seitanidou … (1994)

The molecular mechanisms controlling the process of myelination by Schwann cells remain elusive, despite recent progress in the identification and characterization of genes encoding myelin components (reviewed in ref. 1). We have created a null allele in the mouse Krox-20 gene, which encodes a zinc-finger transcription factor, by in-frame insertion of the Escherichia coli lacZ gene, and have shown that hindbrain segmentation is affected in Krox-20-/- embryos. We demonstrate here that Krox-20 is also activated in Schwann cells before the onset of myelination and that its disruption blocks Schwann cells at an early stage in their differentiation, thus preventing myelination in the peripheral nervous system. In Krox-20-/- mice, Schwann cells wrap their cytoplasmic processes only one and a half turns around the axon, and although they express the early myelin marker, myelin-associated glycoprotein, late myelin gene products are absent, including those for protein zero and myelin basic protein. Therefore Krox-20 is likely to control a set of genes required for completion of myelination in the peripheral nervous system.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 9 June 2016

Publication date (Electronic): 13 June 2016

Publication date (Print): August 2016

Publication date PMC-release: 13 December 2016

Volume: 19

Issue: 8

Pages: 1060-1072

Affiliations

[1 ]Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

[2 ]Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands

[3 ]Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

[4 ]Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

[5 ]Department of Biological Science, Rutgers University, Newark, NJ, USA

[6 ]VIB Center for the Biology of Disease, KU Leuven Department of Human Genetics, Leuven, Belgium

[7 ]Department of Neurology, Program in Biomedical and Neurosciences, University of California, San Francisco, CA, USA

[8 ]Laboratory of Molecular Biology (Celgen), KU Leuven Department of Development and Regeneration, Leuven, Belgium

[9 ]Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

[10 ]Key Laboratory of Birth Defects, Children’s Hospital of Fudan University, Shanghai, China

Author notes

Correspondence: Dr. Q. Richard Lu, Department of Pediatrics, Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Cincinnati Children’s Hospital Medical Center, OH 45229, USA; Tel: 513-636-7684; Fax: 513-803-0783; richard.lu@ 123456cchmc.org

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Manuscript ID: NIHMS786838

DOI: 10.1038/nn.4322

PMC ID: 4961522

PubMed ID: 27294509

SO-VID: 95596373-549b-420b-a924-8d3faaad39c6

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Zeb2 Recruits HDAC-NuRD to Inhibit Notch and Controls Schwann Cell Differentiation and Remyelination

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Neuronal Signaling

Most cited references 44

The origin and development of glial cells in peripheral nerves.

Myelination of the nervous system: mechanisms and functions.

Krox-20 controls myelination in the peripheral nervous system.

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