Axonal regulation of myelination by neuregulin 1

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Neuregulins comprise a family of epidermal growth factor-like ligands that interact with ErbB receptor tyrosine kinases to control many aspects of neural development. One of the most dramatic effects of neuregulin-1 is on glial cell differentiation. The membrane-bound neuregulin-1 type III isoform is an axonal ligand for glial ErbB receptors that regulates the early Schwann cell lineage, including the generation of precursors. Recent studies have shown that the amount of neuregulin-1 type III expressed on axons also dictates the glial phenotype, with a threshold level triggering Schwann cell myelination. Remarkably, neuregulin-1 type III also regulates Schwann cell membrane growth to adjust myelin sheath thickness to match axon caliber precisely. Whether this signaling system operates in central nervous system myelination remains an open question of major importance for human demyelinating diseases.

Introduction

Reciprocal interactions between neurons and glia are crucial for the organization and function of the nervous system, from neurogenesis in embryonic development to synaptic plasticity in the adult brain. Glial cells that synthesize myelin are essential for normal motor and cognitive functions, with the fine tuning of myelination contributing to the millisecond precision of the nervous system [1]. Furthermore, myelin-forming glial cells are also required for the long-term integrity of axons, independently of myelin itself [2, 3]. Axons, in turn, crucially regulate the behavior of myelinating glia: that is, Schwann cells and oligodendrocytes. However, the molecular mechanisms by which neurons and glial cells communicate remain poorly understood.

In this review, we describe recent progress in elucidating the mechanisms by which motor and sensory axons in the peripheral nervous system (PNS) regulate the development and differentiation of Schwann cells, most strikingly during myelination. Unexpectedly, a single growth factor, neuregulin-1 (NRG1), has emerged as the pivotal signal that controls Schwann cells at every stage of the lineage.

Section snippets

Neuregulin-1 and ErbB receptors

The Neuregulin-1 (NRG1) family comprises more than 15 membrane-associated and secreted proteins [4, 5•]. These are derived from one of the largest mammalian genes (on human chromosome 8p22 and mouse chromosome 8A3) and are generated by use of multiple transcription sites and by extensive alternative RNA splicing [6]. All NRG1 isoforms share an epidermal growth factor (EGF)-like signaling domain that is necessary and sufficient for activation of their receptors. NRG1 isoforms are subdivided into

The role of NRG1 in Schwann cell myelination

NRG1 has a crucial role at essentially every developmental stage of Schwann cells, as first indicated by both culture studies and analysis of knockout mice [21, 22••]. These functions include promoting the gliogenic fate of trunk neural crest cells, the migration of Schwann cell precursors (SCP) along axons, and their subsequent proliferation and survival induced by axons. A recent study, analyzing zebrafish ErbB mutants, strongly supports the key role of NRG1–ErbB signaling in SCP

A role for neurotrophins in axonal NRG1 signaling

Neurotrophins exert multiple effects on developing glia, including Schwann cells and oligodendrocytes. A remarkable ability to stimulate Schwann cell differentiation in vivo was observed by Griffin and co-workers [50], who found that the injection of glial-derived growth factor (GDNF) into rats caused non-myelinating Schwann cells to proliferate and even to myelinate some of the very small caliber C-fiber axons. These experiments do not distinguish between a direct effect on glia and an

The role of NRG1 in oligodendrocyte development

An obvious question is whether NRG1 type III also regulates oligodendrocyte myelination — this important issue is yet to be resolved. However, several studies suggest that NRG1–ErbB signaling might regulate oligodendrocyte development and provide insights into its potential role during differentiation.

Initial studies in which oligodendrocyte progenitor cell (OPC) cultures were supplemented with soluble NRG1 isoforms suggested that NRG1 has trophic and mitogenic effects on cells in the

Clinical implications

Null mutations of the NRG1 gene and its receptors are embryonically lethal in mice [7], suggesting that human NRG1 loss-of-functions are unlikely to be a primary cause of disease. However, the many roles of NRG1 in glial cell development suggest that dysregulated NRG1 expression (or abnormal Nrg1-ErbB-PI3K signaling) contributes to disorders of myelin as a disease modifier or a genetic risk factor. Although this is an interesting possibility, it remains speculative as no evidence directly links

Outlook and conclusions

The identification of NRG1 as the axonal signal that drives the entire Schwann cell lineage, including myelination, is an important milestone that will facilitate elucidation of the mechanisms that underlie the morphogenetic and transcriptional events of myelination. In the PNS, important remaining questions include how NRG1-dependent activation of PtdIns 3-kinase initially promotes proliferation but later drives differentiation of Schwann cells, how NRG1 signaling strength regulates the binary

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Owing to space limitations, we regret any omissions in citing other relevant publications. We thank C Birchmeier, D Falls, C Lai, J Loeb, M Schwab, and C Taveggia for insightful discussions and for comments on the manuscript. Work from the authors’ laboratories cited in this review has been supported by grants from the Duetsche Forschungsgemeinschaft (Center for the Molecular Physiology of the Brain), National Institutes of Health, and the National Multiple Sclerosis Society.

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