Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity.
Notch signaling is central to vertebrate development, and analysis of Notch has provided important insights into pathogenetic mechanisms in the CNS and many other tissues. However, surprisingly little is known about the role of Notch in the development and pathology of Schwann cells and peripheral nerves. Using transgenic mice and cell cultures, we found that Notch has complex and extensive regulatory functions in Schwann cells. Notch promoted the generation of Schwann cells from Schwann cell precursors and regulated the size of the Schwann cell pool by controlling proliferation. Notch inhibited myelination, establishing that myelination is subject to negative transcriptional regulation that opposes forward drives such as Krox20. Notably, in the adult, Notch dysregulation resulted in demyelination; this finding identifies a signaling pathway that induces myelin breakdown in vivo. These findings are relevant for understanding the molecular mechanisms that control Schwann cell plasticity and underlie nerve pathology, including demyelinating neuropathies and tumorigenesis.
Woodhoo
Ashwin
A
Department of Cell and Developmental Biology, University College London, UK.
Alonso
Maria B Duran
MB
Droggiti
Anna
A
Turmaine
Mark
M
D'Antonio
Maurizio
M
Parkinson
David B
DB
Wilton
Daniel K
DK
Al-Shawi
Raya
R
Simons
Paul
P
Shen
Jie
J
Guillemot
Francois
F
Radtke
Freddy
F
Meijer
Dies
D
Feltri
M Laura
ML
Wrabetz
Lawrence
L
Mirsky
Rhona
R
Jessen
Kristján R
KR
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003711:Demyelinating Diseases / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000502:physiology; D020890:Neuregulin-1 / Q000378:metabolism; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000196:embryology / Q000254:growth & development; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors
D051767:Early Growth Response Protein 2; D006023:Glycoproteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D051880:Receptors, Notch; C490581:Nrg1 protein, mouse; C490580:Nrg1 protein, rat; C497571:Rbpj protein, mouse; C524056:Erbb2 protein, mouse; C483804:Erbb2 protein, rat