Review
Neuregulin and ErbB receptor signaling pathways in the nervous system

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Abstract

The neuregulins are a complex family of factors that perform many functions during neural development. Recent experiments have shown that neuregulins promote neuronal migration and differentiation, and regulate the selective expression of neurotransmitter receptors in neurons and at the neuromuscular junction. They also regulate glial commitment, proliferation, survival and differentiation. At interneuronal synapses, neuregulin ErbB receptors associate with PDZ-domain proteins at postsynaptic densities where they can modulate synaptic plasticity. How this combinatorial network — comprising many neuregulin ligands that signal through distinct combinations of dimeric ErbB receptors — elicits its multitude of biological effects is beginning to be resolved.

Introduction

The neuregulins (NRGs) are a family of proteins containing an epidermal growth factor (EGF)-like motif that activates membrane-associated tyrosine kinases related to the EGF receptor (known as ErbB-1). Initially, NRG-1 was found to function in the nervous system in the proliferation of Schwann cells, and in the regulation of nicotinic acetylcholine receptor (AChR) transcription at the neuromuscular junction (NMJ). More recently, the NRGs have been found to regulate early fate determination, differentiation, migration and survival of satellite cells, Schwann cells and oligodendrocytes. In neurons, NRGs promote neuronal migration, and selectively increase the expression of other neurotransmitter receptors.

Much of our current knowledge about NRG signaling pathways in the nervous system originates from studies of EGF and NRG actions in non-neural cell types. At present, four genes encoding NRGs have been identified in vertebrates (Fig. 1). Alternate RNA splicing further enhances the complexity of this EGF-like family. NRG-1–4 bind preferentially to the ErbB-3 and -4 receptors, which then form homo- or heterodimers by recruiting either ErbB-1 or -2 co-receptors to propagate signaling (see [1]). ErbB-2 is thought to be an important co-receptor on the basis of in vivo and in vitro experiments.

Like other factors signaling through receptor tyrosine kinases (RTKs), NRG binding to its receptor promotes tyrosine cross-phosphorylation, the association of proteins containing phosphotyrosine-binding or Src homology-2 domains with the phosphorylated residues, and the activation of intracellular effector pathways that mediate the specific biological responses. Notably, many of the effector molecules used by NRGs in the mammalian nervous system are related to those used by the EGF ligands in Drosophila and Caenorhabditis elegans.

In this review, we will summarize the latest findings regarding the spectrum of NRG actions and the signaling pathways used in neurons, glia and at muscle synapses. We will discuss studies that reveal how different biological mechanisms have evolved to regulate the complexity and specificity of the NRG–ErbB signaling pathway. These studies are beginning to address why so many NRG isoforms are generated, and how distinct isoforms elicit specific biological responses.

Section snippets

Structural similarities between NRGs

To date ten genes have been found to encode EGF or EGF-like ligands in vertebrates (see Fig. 1b). The EGF-like domain of NRG is required for receptor binding, and on its own is sufficient to elicit ErbB receptor dimerization, tyrosine phosphorylation and the activation of downstream signaling pathways. This domain contains roughly 50 amino acids and is characterized by three pairs of cysteines that are important for its tertiary structure and biological function. As yet, the criteria to

Signaling in neurons

Neurons express different combinations of NRG-1–3 and ErbB receptors during development. Unfortunately, targeted null mutations of Nrg-1, erbB-2 and erbB-4 result in an embryonic-lethal cardiac phenotype at about embryonic day 10 (E10), thereby impeding the study of these factors in later neural development. Nonetheless, early in development, NRG-1 and ErbB-2 null mice have reduced numbers of cranial sensory neurons, and ErbB-4-deficient mice have abnormal targeting of cranial sensory and motor

NRG and ErbB diversity

Duplications of an ancestral gene have resulted in at least four NRG genes in mammals, and alternate use of transcriptional promoters and splice sites markedly increases the number of NRG isoforms derived from these loci. Although the EGF-like domain alone is sufficient to elicit ErbB phosphorylation and mimic many of the biological effects of the full-length factors, the importance of the other NRG structural domains are beginning to be identified. For example, the ectodomains of NRG-1 can

Conclusions

The NRG family exerts a multitude of biological effects in the nervous system, often with seemingly opposing actions (proliferation versus differentiation), by signaling through a limited number of ErbB receptors. Our knowledge of the complexity of NRG ligands and their receptors, and the distinct mechanisms that they use to generate signaling specificity, has increased greatly in the past few years as a result of experiments performed in numerous cell types and organisms. Studies of the

Update

Recent experiments demonstrate the importance of the serine/threonine cylin-dependent kinase 5 (Cdk5), and its required co-activator p35, in the NRG-dependent regulation of AChRs [86••]. Cdk5 and p35 are highly expressed in embryonic muscles, and while their levels decrease with development, both proteins concentrate at the NMJs. Cdk5/p35 associate with and phosphorylate serine residues in ErbB receptors on muscle membranes. This kinase activity is important, because Cdk5 inhibition attenuates

Acknowledgements

We thank Dorothy Turetsky and Steven Carroll for their helpful comments on the manuscript, and K Vasudevan and S Kinsley for assistance with figures.

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

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