Zeb2 is essential for Schwann cell differentiation, myelination and nerve repair.
Schwann cell development and peripheral nerve myelination require the serial expression of transcriptional activators, such as Sox10, Oct6 (also called Scip or Pou3f1) and Krox20 (also called Egr2). Here we show that transcriptional repression, mediated by the zinc-finger protein Zeb2 (also known as Sip1), is essential for differentiation and myelination. Mice lacking Zeb2 in Schwann cells develop a severe peripheral neuropathy, caused by failure of axonal sorting and virtual absence of myelin membranes. Zeb2-deficient Schwann cells continuously express repressors of lineage progression. Moreover, genes for negative regulators of maturation such as Sox2 and Ednrb emerge as Zeb2 target genes, supporting its function as an 'inhibitor of inhibitors' in myelination control. When Zeb2 is deleted in adult mice, Schwann cells readily dedifferentiate following peripheral nerve injury and become repair cells. However, nerve regeneration and remyelination are both perturbed, demonstrating that Zeb2, although undetectable in adult Schwann cells, has a latent function throughout life.
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.|University Medical Center Göttingen (UMG), Department of Clinical Neurophysiology, Göttingen, Germany.
Susanne
S
Quintes
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Bastian G
BG
Brinkmann
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Madlen
M
Ebert
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
Franziska
F
Fröb
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Theresa
T
Kungl
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Friederike A
FA
Arlt
Institute for Cell and Neurobiology, Center for Anatomy, Charité Universitätsmedizin Berlin, Berlin, Germany.
Victor
V
Tarabykin
Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, KU Leuven, Leuven, Belgium.|Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Danny
D
Huylebroeck
Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
Dies
D
Meijer
Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Zürich, Switzerland.
Ueli
U
Suter
Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
Michael
M
Wegner
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.|University Medical Center Göttingen (UMG), Department of Clinical Neurophysiology, Göttingen, Germany.
Michael W
MW
Sereda
Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.
Klaus-Armin
KA
Nave
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002454:Cell Differentiation / Q000502:physiology*; D051767:Early Growth Response Protein 2 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
D051767:Early Growth Response Protein 2; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2