Novel Signals Controlling Embryonic Schwann Cell Development, Myelination and Dedifferentiation

Department of Cell and Developmental Biology, University College London, London, UK.
Journal of the Peripheral Nervous System (Impact Factor: 2.76). 07/2008; 13(2):122-35. DOI: 10.1111/j.1529-8027.2008.00168.x
Source: PubMed


Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non-myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann cell dedifferentiation involves activation of specific receptors, intracellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann cell, times Schwann cell generation, controls Schwann cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.

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Available from: Kristján R Jessen
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    • "Growth factors, such as neuregulin-1 (NRG1). and adhesion molecule ligands, including various integrin ones, which are primarily produced by peripheral neurons, bind to their cognate receptors on Schwann cells, and their receptor activity regulates myelination (Nave and Salzer, 2006; Mirsky et al., 2008; Taveggia et al., 2010; Pereira et al., 2012; Miyamoto and Yamauchi, 2014). Tyro3 is a receptor tyrosine kinase member belonging to the Tyro3, Axl, and "
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    ABSTRACT: During early development of the peripheral nervous system, Schwann cell precursors proliferate, migrate, and differentiate into premyelinating Schwann cells. After birth, Schwann cells envelop neuronal axons with myelin sheaths. While some molecular mechanisms underlying myelination by Schwann cells have been identified, the whole picture still remains unclear. Here, we describe that signaling through Tyro3 receptor tyrosine kinase and its binding partner, Fyn nonreceptor cytoplasmic tyrosine kinase, is involved in the myelination by Schwann cells. Impaired formation of myelin segments is observed in Schwann cell-neuronal cultures established from Tyro3 knockout mouse dorsal root ganglia (DRGs). Indeed, Tyro3 knockout mice exhibit reduced myelin thickness. In affinity chromatography, Fyn has been identified as the binding partner of the Tyro3 intracellular domain and the activity of Fyn is down-regulated in Tyro3 knockout mice, suggesting that Tyro3, acting through Fyn, regulates myelination. Ablating Fyn in mice results in reduced myelin thickness. Decreased myelin formation is observed in cultures established from Fyn knockout mouse DRGs. Furthermore, decreased kinase activity levels and altered expression of myelination-associated transcription factors are observed in these knockout mice. These results suggest the involvement of Tyro3 receptor and the binding partner Fyn in Schwann cell myelination. This constitutes a newly recognized, receptor-linked signaling mechanism that can control Schwann cell myelination. © 2015 by The American Society for Cell Biology.
    Full-text · Article · Jul 2015 · Molecular biology of the cell
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    • "During this stage c-Jun, Sox2 and Pax3 are also activated (Doddrell et al., 2012; Jessen and Mirsky, 2008; Kim et al., 2013; Lutz and Barres, 2014; Mirsky et al., 2008 Parkinson et al., 2008; Patodia and Raivich, 2012; Yang et al., 2012). At this time point, SC release chemokines and cytokines to attract haematological immune cells such as macrophages and T-cells (Jessen and Mirsky, 2008; Kato et al., 2013; Lutz and Barres, 2014; Martini et al., 2008; Mietto et al., 2013; Ydens et al., 2013). "
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    DESCRIPTION: Dissertation project using Cre-loxP Merlin-null mice to assess macrophage infiltration and proliferation after peripheral nerve injury
    Full-text · Research · May 2015
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    • "Peripheral nerve myelination is achieved by the plasma membrane of Schwann cells (SCs), the sole glial cells of peripheral nerves, wrapping around axons during perinatal and early postnatal development. In fact, the myelin sheath is a notable outcome of the differentiation of SCs [2, 3, 4]. Once the myelin sheath is formed and matured postnatally, the integrity of the myelin sheath is maintained throughout life unless the nerve is physically or chemically damaged. "
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    ABSTRACT: Schwann cells (SCs) in the peripheral nerves myelinate axons during postnatal development to allow saltatory conduction of nerve impulses. Well-organized structures of myelin sheathes are maintained throughout life unless nerves are insulted. After peripheral nerve injury, unidentified signals from injured nerves drive SC dedifferentiation into an immature state. Dedifferentiated SCs participate in axonal regeneration by producing neurotrophic factors and removing degenerating nerve debris. In this review, we focus on the role of mitogen activated protein kinase family proteins (MAP kinases) in SC dedifferentiation. In addition, we will highlight neuregulin 1 and the transcription factor c-jun as upstream and downstream signals for MAP kinases in SC responses to nerve injury.
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