Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination.
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.
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Lai Man Natalie
0000-0002-7285-3606
LM
Wu
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Jincheng
J
Wang
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Andrea
A
Conidi
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Chuntao
C
Zhao
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Haibo
H
Wang
Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Zachary
Z
Ford
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Liguo
L
Zhang
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Christiane
C
Zweier
Department of Biological Science, Rutgers University, Newark, New Jersey, USA.
Brian G
BG
Ayee
Department of Biological Science, Rutgers University, Newark, New Jersey, USA.
Patrice
P
Maurel
VIB Center for the Biology of Disease, KU Leuven Department of Human Genetics, Leuven, Belgium.
An
0000-0002-8583-1721
A
Zwijsen
Department of Neurology, Program in Biomedical and Neurosciences, University of California, San Francisco, San Francisco, California, USA.
Jonah R
JR
Chan
Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Michael P
MP
Jankowski
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, the Netherlands.|Laboratory of Molecular Biology (Celgen), KU Leuven Department of Development and Regeneration, Leuven, Belgium.
Danny
D
Huylebroeck
Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
Q Richard
QR
Lu
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D019066:Facies; D006627:Hirschsprung Disease / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism*; D008607:Intellectual Disability / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D008831:Microcephaly / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000648:ultrastructure*; D055495:Neurogenesis / Q000502:physiology; D009707:Nucleosomes / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2
D018398:Homeodomain Proteins; D009707:Nucleosomes; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D056284:Histone Deacetylase 1; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex