Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation

Abstract

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.

Negative regulation of myelination: Relevance for development, injury, and demyelinating disease

“…The major events are: axon death, invasion of blood-borne macrophages, collapse of myelin sheaths together with ingestion and breakdown of the myelin material, a transient phase of Schwann cell proliferation, and a reversal of molecular expression from that characteristic of mature myelinating and nonmyelinating cells back to one that resembles the immature state. In the case of myelinating cells this involves downregulation of a large number of genes related to myelination (reviewed in Jessen and Mirsky, 2005;Mirsky et al, 2008;Scherer and Salzer, 2001). This includes enzymes that provide for cholesterol synthesis, structural proteins such as P 0 , myelin basic protein (MBP), and membrane associated proteins such as myelin associated glycoprotein (MAG) and periaxin (Buchstaller et al, 2004;D'Antonio et al, 2006;Leblanc et al, 2005;Nagarajan et al, 2001Nagarajan et al, , 2002Verheijen et al, 2003).…”

“…The loss of the myelin sheath and myelin gene expression, and the reappearance of a set of protein markers of immature cells (L1, NCAM, p75NTR, GFAP and others), means that immature cells in developing nerves and ''denervated cells'' (the cells in the distal stump of cut nerves) show obvious similarities (reviewed in Jessen and Mirsky, 2005;Mirsky et al, 2008). In major features therefore this process represents dedifferentiation.…”

Wnt/Rspondin/β-catenin signals control axonal sorting and lineage progression in Schwann cell development

“…In particular, Fyn kinase has been shown to control cytoskeletal modifications and lamellae extension in oligodendrocytes (44,45). The identified transcription factors could also directly affect SC differentiation: Jun is a known negative regulator of SC differentiation and myelination (2,46). Olig1 promotes oligodendrocyte differentiation (47), but a role in SCs has not been addressed.…”

“…Subsequently, large sorted axons become myelinated, whereas multiple small axons remain unsorted and surrounded by nonmyelinating SCs (Remak bundles). The precise timing of radial sorting is instrumental for correct nerve development and homeostasis and is achieved through signaling cues provided by axons and by the extracellular environment (1)(2)(3). Axonal Neuregulin-1 type III acts through the ErbB/Shp2 signaling system to control SC proliferation, migration along nerves, and terminal differentiation (4)(5)(6).…”

Neuregulin1 administration increases axonal elongation in dissociated primary sensory neuron cultures

“…NRG1 is a family of proteins encoded by a single gene that, through the existence of several promoters and alternative splicing, is expressed into more than 20 different isoforms [15,16]. Some of these isoforms are known to be strongly involved in the regulation of myelination in the peripheral nervous system [17,18] and the pro-motion of gliogenic fate of neural crest cells during development [19,20]. Other isoforms promote the dedifferentiation and migration of SCs after nerve lesion and their subsequent proliferation and sur-vival mediated by axonal signalling [21][22][23].…”