Axonal regulation of myelination by neuregulin 1
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.
References (72)
Axon-glia interactions: building a smart nerve fiber
Curr Biol
(1997)Neuregulins: functions, forms, and signaling strategies
Exp Cell Res
(2003)- et al.
The N-terminal region of neuregulin isoforms determines the accumulation of cell surface and released neuregulin ectodomain
J Biol Chem
(2001) - et al.
Multiple novel transcription initiation sites for NRG1
Gene
(2004) - et al.
ErbB2 pathways in heart and neural diseases
Trends Cardiovasc Med
(2003) - et al.
Role of neuregulins in glial cell development
Glia
(2000) - et al.
An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors
Mol Cell
(2003) - et al.
GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors
Neuron
(1996) - et al.
The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation
J Neurosci
(2005) - et al.
Transmembrane neuregulins interact with LIM kinase 1, a cytoplasmic protein kinase implicated in development of visuospatial cognition
J Biol Chem
(1998)
Neuregulin, a factor with many functions in the life of a Schwann cell
Bioessays
In vivo analysis of Schwann cell programmed cell death in the embryonic chick: regulation by axons and glial growth factor
J Neurosci
Target size regulates calibre and myelination of sympathetic axons
Nature
A dual role of erbB2 in myelination and in expansion of the Schwann cell precursor pool
J Cell Biol
Axonal swellings and degeneration in mice lacking the major proteolipid of myelin
Science
Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination
Nat Genet
Neuregulins: versatile growth and differentiation factors in nervous system development and human disease
Brain Res Brain Res Rev
Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease
Proc Natl Acad Sci USA
Isoform-specific expression and function of neuregulin
Development
Evaluation of the contributions of ADAMs 9, 12, 15, 17, and 19 to heart development and ectodomain shedding of neuregulins beta1 and beta2
Dev Biol
Generation and characterization of neuregulin-2-deficient mice
Mol Cell Biol
The deaf and the dumb: the biology of ErbB-2 and ErbB-3
Exp Cell Res
Back signaling by the Nrg-1 intracellular domain
J Cell Biol
A reciprocal cell-cell interaction mediated by NT-3 and neuregulins controls the early survival and development of sympathetic neuroblasts
Neuron
The origin and development of glial cells in peripheral nerves
Nat Rev Neurosci
erbb3 and erbb2 are essential for Schwann cell migration and myelination in zebrafish
Curr Biol
Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins
J Neurosci
Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses
Neuron
On the union of the fifth cervical nerve with the superior cervical ganglion
J Physiol
Control of myelin formation by axon caliber (with a model of the control mechanism)
J Comp Neurol
Neuregulin-1 type III determines the ensheathment fate of axons
Neuron
On the areas of the axis cylinder and medullary sheath as seen in cross sections of the spinal nerves of vertebrates
J Comp Neurol
Axonal neuregulin-1 regulates myelin sheath thickness
Science
Neuregulin 1-erbB signaling is necessary for normal myelination and sensory function
J Neurosci
ErbB2 signaling in Schwann cells is mostly dispensable for maintenance of myelinated peripheral nerves and proliferation of adult Schwann cells after injury
J Neurosci
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