@article{6b2d583a7f25419b82eb10f4cd782fce,
title = "Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination",
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.",
author = "Wu, {Lai Man Natalie} and Jincheng Wang and Andrea Conidi and Chuntao Zhao and Haibo Wang and Zachary Ford and Liguo Zhang and Christiane Zweier and Ayee, {Brian G.} and Patrice Maurel and An Zwijsen and Chan, {Jonah R.} and Jankowski, {Michael P.} and Danny Huylebroeck and Lu, {Q. Richard}",
note = "Funding Information: The authors thank X. Chen and Z. Ma for technical support and initial observation of Zeb2 mutants. We thank A. Rauch for discussing ZEB2 missense mutations in MOWS patients, J. Svaren and E. Hurlock for suggestions and G. Verstappen and L. van Grunsven for initial study of Zeb2R22GNuRD interactions. We are grateful to K.-A. Nave for communications of unpublished data. We also thank R. Kopan (University of Cincinnati) and A.J. Capiobianco (University of Miami) for the TP-1 reporter and lentiviral DN-MAML constructs and to J.W. Schneider and E.N. Olson (University of Texas Southwestern Medical Center)) for Notch-GFP reporter mice and Flag-HRT2/Hey2 vectors. This study was funded in part by grants from the US National Institute of Health R01NS072427 and R01NS075243 to Q.R.L., R01NS062796 to J.R.C. and R01AR064551 to M.P.J., and from the National Multiple Sclerosis Society (NMSS-4727) to Q.R.L. L.M.N.W. was supported by an NMSS Postdoctoral Fellowship (FA 2045A1/T). The work was also supported by Belspo grant IAP7-07 DevRepair, the Research Council of KU Leuven (GOA-11/012), FWO-V (G.0782.14), the type 3 large-infrastructure support InfraMouse by the Hercules Foundation (ZW09-03) and Erasmus MC start-up funds, to D.H. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",
year = "2016",
month = aug,
day = "1",
doi = "10.1038/nn.4322",
language = "English (US)",
volume = "19",
pages = "1060--1072",
journal = "Nature neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "8",
}