Axonal regulation of myelination by neuregulin 1 Klaus-Armin Nave1,2 and James L Salzer3 Neuregulins comprise a family of epidermal growth factor-like In this review, we describe recent progress in elucidating ligands that interact with ErbB receptor tyrosine kinases to the mechanisms by which motor and sensory axons in the control many aspects of neural development. One of the most peripheral nervous system (PNS) regulate the develop- dramatic effects of neuregulin-1 is on glial cell differentiation. ment and differentiation of Schwann cells, most strikingly The membrane-bound neuregulin-1 type III isoform is an axonal during myelination. Unexpectedly, a single growth factor, ligand for glial ErbB receptors that regulates the early Schwann neuregulin-1 (NRG1), has emerged as the pivotal signal cell lineage, including the generation of precursors. Recent that controls Schwann cells at every stage of the lineage. studies have shown that the amount of neuregulin-1 type III expressed on axons also dictates the glial phenotype, with a Neuregulin-1 and ErbB receptors threshold level triggering Schwann cell myelination. The Neuregulin-1 (NRG1) family comprises more than Remarkably, neuregulin-1 type III also regulates Schwann cell 15 membrane-associated and secreted proteins [4,5]. membrane growth to adjust myelin sheath thickness to match These are derived from one of the largest mammalian axon caliber precisely. Whether this signaling system operates genes (on human chromosome 8p22 and mouse chromo- in central nervous system myelination remains an open some 8A3) and are generated by use of multiple tran- question of major importance for human demyelinating scription sites and by extensive alternative RNA splicing diseases. [6]. All NRG1 isoforms share an epidermal growth factor Addresses (EGF)-like signaling domain that is necessary and suffi- 1 Max Planck Institute of Experimental Medicine, D-37075 Goettingen, cient for activation of their receptors. NRG1 isoforms are Germany subdivided into several subtypes on the basis of their 2 Hertie Institute of Multiple Sclerosis Research, Goettingen, Germany 3 Departments of Cell Biology and Neurology, and the Molecular distinct amino-termini [4,7]. NRG1 type I (also known as Neurobiology Program, Skirball Institute of Biomolecular Medicine, New heregulin, neu differentiation factor, or acetylcholine York University School of Medicine, New York, NY 10016, USA receptor-inducing activity [ARIA]) and NRG1 type II (also known as glial growth factor [GGF]) have N-term- Corresponding author: Nave, Klaus-Armin ([email protected]) inal immunoglobulin-like domains. Transmembrane forms of NRG1 undergo proteolytic cleavage by metal- Current Opinion in Neurobiology 2006, 16:492–500 loproteinases (MP), including TACE (tumor-necrosis factor-a-converting enzyme) [8]. As a consequence, This review comes from a themed issue on NRG1 type I and II are shed from the neuronal cell Neuronal and glial cell biology Edited by Kelsey C Martin and Elior Peles surface and function as paracrine signaling molecules (schematically depicted in Figure 1). NRG1 type III is Available online 7th September 2006 defined by its cysteine-rich domain (CRD), which func- 0959-4388/$ – see front matter tions as a second transmembrane domain. Consequently, # 2006 Elsevier Ltd. All rights reserved. NRG1 type III remains tethered to the cell surface after cleavage and functions as a juxtacrine signal [9]. In DOI 10.1016/j.conb.2006.08.008 addition, exons encoding shorter amino termini of NRG1 have been identified by sequence analysis (referred to as types IV–VI), but these isofoms have Introduction not been further characterized [10]. NRG1 expression Reciprocal interactions between neurons and glia are is not specific to the nervous system, it also has a major crucial for the organization and function of the nervous role in cardiac and mammary tissue development system, from neurogenesis in embryonic development to (reviewed in [11]). Indeed, mice lacking NRG1, or its synaptic plasticity in the adult brain. Glial cells that receptors (ErbB2, ErbB3 and ErbB4), are embryonic synthesize myelin are essential for normal motor and lethal because NRG1–ErbB signaling is essential for cognitive functions, with the fine tuning of myelination cardiac development. contributing to the millisecond precision of the nervous system [1]. Furthermore, myelin-forming glial cells are Within the nervous system, NRG1 types I and III are the also required for the long-term integrity of axons, inde- most abundant forms and have been detected in many pendently of myelin itself [2,3]. Axons, in turn, crucially projection neurons, most notably in spinal motor neurons regulate the behavior of myelinating glia: that is, Schwann and dorsal root ganglia (DRG) neurons, but also in glia cells and oligodendrocytes. However, the molecular [4,12]. In addition to the axon–glia signaling detailed mechanisms by which neurons and glial cells commu- below, the proposed functions of NRG1 include the devel- nicate remain poorly understood. opment of motor endplates, migration of interneurons, and Current Opinion in Neurobiology 2006, 16:492–500 www.sciencedirect.com Axonal regulation of myelination by neuregulin 1 Nave and Salzer 493 Figure 1 NRG1 isoforms: membrane disposition and signalling. (a) Types I and II are synthesized as single pass transmembrane proteins; Type III has two transmembrane domains. (b) With metalloproteinase (MP) cleavage, types I and II are shed as paracrine signals, type III remains tethered through its cysteine rich domain (CRD) and is a juxtacrine signal; this cleavage is enhanced by neurotrophins released by Schwann cells. The cytoplasmic domain undergoes further cleavage stimulated by binding of ErbB receptors to NRG1, followed by translocation to the nucleus. See [4]for additional details. synaptogenesis and synaptic plasticity in the CNS [5]. adaptor molecules and activation of downstream signaling Many NRG1-expressing neurons also express transcripts pathways (see below). Whereas Schwann cells principally for NRG2 and NRG3, two structurally related growth express ErbB2 and ErbB3, cells in the oligodendrocyte factors with EGF-like signaling domains, the function of lineage express all three ErbB receptors, in a developmen- which in the nervous system remains largely unknown tally regulated manner, in addition to the EGFR (ErbB1), [12,13]. indicating significant complexity of potential ErbB recep- tor heterodimers and downstream signaling events in these ErbB receptors cells [16,17]. NRG1 isoforms mediate their effects by binding to ErbB receptors, members of the EGF receptor superfamily [14]. NRG1 ‘back signaling’ NRG1 binds to either ErbB3, which lacks an active kinase Intriguingly, NRG1 might also signal bidirectionally. Bind- domain, or ErbB4, which has such a kinase domain; each ing of recombinantly produced ‘soluble’ ErbB receptors to receptor, in turn, can heterodimerize with ErbB2, which membrane-bound NRG1 type III of transfected neurons cannot bind NRG1 directly but also has an active kinase results in proteolytic cleavage of NRG1, releasing its domain. ErbB receptors dimerize not by virtue of a brid- cytoplasmic C-terminal domain (CTD) from the mem- ging effect of NRG1, but following a ligand-activated brane [18]. Remarkably, the CTD then rapidly translocates conformational change in the ectodomain of ErbB3 or into the cell nucleus of the cultured neurons where it ErbB4 [15]. Crystallographic data indicate that ErbB2 activates transcription and enhances survival. Whether constitutively exposes a dimerization loop required to NRG1 ‘backsignaling’ occurs in vivo, particularly when form heterodimers with ligand-activated ErbB3 or ErbB4 NRG1 expressed on the axon is engaged by ErbB receptors receptors. Because the ability of ErbB2 to form homodi- of myelinating glia, remains to be established. It will also be mers is poor, and ErbB4 is minimally expressed by important to determine whether loss of the anti-apoptotic Schwann cells, ErbB2–ErbB3 is the relevant NRG1 effect of the CTD is normally responsible for the degen- Schwann cell receptor. NRG1 binding induces ErbB2– eration of dorsal root ganglion (DRG) and motor neurons ErbB3 heterodimer formation, which leads to receptor that is observed in NRG1 null mutant mice. Alternatively, cross-phosphorylation, recruitment of SH3-containing conventional NRG1 (forward) signaling could elicit www.sciencedirect.com Current Opinion in Neurobiology 2006, 16:492–500 494 Neuronal and glial cell biology reciprocal trophic support of ensheathed axons, such as indicate that final matching of SCPs to axons is mediated through NRG1-stimulated release of neurotrophins by glia through competition for a NRG1-mediated survival sig- [19]. Finally, the cytoplasmic tail of NRG1 has been nal [24–26]. NRG1 type III is the key isoform required reported to interact directly with LIM kinase, a regulator for SCP survival and migration during early embryogen- of the actin cytoskeleton [20]; the biological significance of esis [26]. this interaction is not yet established. Threshold levels of NRG1 type III are an instructive The role of NRG1 in Schwann cell myelination signal for myelination NRG1 has a crucial role at essentially every develop- Once generated, SCPs differentiate into mature Schwann mental stage of Schwann cells, as first indicated by both cells that either ensheath multiple small, unmyelinated culture studies and analysis of knockout mice [21,22]. axons, forming a Remak bundle, or sort larger axons into a These