Notch controls embryonic Schwann cell differentiation, postnatal myelination and adult plasticity

• Published in: Nature neuroscience Vol. 12; no. 7; pp. 839 - 847
• Main Authors: Woodhoo, Ashwin, Alonso, Maria B Duran, Droggiti, Anna, Turmaine, Mark, D'Antonio, Maurizio, Parkinson, David B, Wilton, Daniel K, Al-Shawi, Raya, Simons, Paul, Shen, Jie, Guillemot, Francois, Radtke, Freddy, Meijer, Dies, Feltri, M Laura, Wrabetz, Lawrence, Mirsky, Rhona, Jessen, Kristján R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2009; Nature Publishing Group
• Subjects: Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell differentiation; Cell Differentiation - physiology; Cell Proliferation; Cells; Cells, Cultured; Cellular signal transduction; Coculture Techniques; Demyelinating Diseases - metabolism; Early Growth Response Protein 2 - genetics; Early Growth Response Protein 2 - metabolism; Embryos; Glycoproteins - metabolism; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Medical research; Mice; Mice, Transgenic; Myelin Sheath - physiology; Nerve Tissue Proteins - metabolism; Nervous system; Neural Crest - cytology; Neural Crest - physiology; Neuregulin-1 - metabolism; Neurobiology; Neurosciences; Pathology; Peripheral Nerve Injuries; Peripheral Nerves - embryology; Peripheral Nerves - growth & development; Physiological aspects; Proteins; Rats; Receptor, ErbB-2 - metabolism; Receptors, Notch - metabolism; Schwann cells; Schwann Cells - cytology; Schwann Cells - physiology; Signal Transduction; Time Factors; Tumorigenesis; United States; Italy; United Kingdom; United Kingdom > UK
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.2323

Although the role of Notch signaling in CNS glial development is well established, its participation in peripheral glial development is still unclear. This paper shows that Notch signaling regulates the differentiation of Schwann cell precursors and the proliferation of Schwann cells, and acts as a break on myelination of peripheral nerves. 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.