Neuregulins in Development

INTRODUCTION Groenen et al., 1994). In addition to EGF and the NRGs, this family includes transforming growth factor a (TGFa) (Kumar et al., 1995), amphiregulin (Shoyab et al., 1989), The neuregulins (NRGs) are a set of repeatedly rediscripto (Ciardiello et al., 1991), heparin-binding EGF-like covered growth factors. Alternatively spliced products growth factor (HB-EGF) (Higashiyama et al., 1991), betaof a single gene, these proteins have been independently cellulin (Shing et al., 1993), epiregulin (Toyoda et al., identified and purified as glial growth factor (GGF) 1995), and at least one yet-to-be-named protein (Chang (Brockes et al., 1980; Lemke and Brockes, 1984; Goodearl and Gilbert, 1994). All of these proteins are products of et al., 1993), as acetylcholine receptor inducing activity distinct, but structurally related genes. It is important (ARIA) (Falls et al., 1990, 1993), as neu differentiation to keep the expanse of this EGF family in mind when factor (NDF) (Peles et al., 1992), and as heregulin (HRG) interpreting the mutant mouse phenotypes described be(Holmes et al., 1992). The common identity of these low, since some of the proteins in the family bind to the agents was ultimately revealed only through cDNA clonsame cell surface receptor(s), and in turn, these receptors ing, which was achieved for NDF and HRG in 1992 (Wen often heterodimerize with and activate one another (Caret al., 1992; Holmes et al., 1992), and for ARIA and GGF raway and Cantley, 1994; Riese et al., 1995). in 1993 (Falls et al., 1993; Marchionni et al., 1993). The fact that essentially the same protein, now given the conStructure of the neuregulins. The diversity of the sensus name neuregulin (Marchionni et al., 1993), could larger EGF family is matched by the diversity of protein be encountered and christened multiple times is both a products produced by the neuregulin gene. This gene, reflection of its diverse bioactivities and of the diversity located on the short arm of human chromosome 8 (Orrof its isoforms, which differ significantly in molecular Urtreger et al., 1993), is subject to a series of alternative weight (Lemke, 1993). In this review, I summarize our splicing reactions that lead to more than 15 distinct isocurrent knowledge of NRG structure and action, as well forms, some membrane-bound and some soluble (see as the status of the NRG receptors of the ErbB family. I Fig. 1). The number of identified NRG variants continues also consider recent studies in mutant mouse embryos, to grow as new protein isoforms are purified, and new which provide new insights into the roles that the NRGs cDNAs corresponding to differentially spliced mRNAs and their receptors play in the development of both neuare cloned (Falls et al., 1993; Marchionni et al., 1993; Wen ral and extraneural tissues. et al., 1994; Ho et al., 1995; Burgess et al., 1995). There are four distinct sites within the coding region of the NRG gene that are distinguished either by (a) the NEUREGULINS multiplicity of alternative splicing reactions that occur at the site; or (b) the very different protein structures that are generated through a single alternative splice at the The neuregulins are part of a larger family of proteins site. Moving from N-terminus to C-terminus, these splicwhose members are all structurally related to the granding hotspots (SHS1-4 in Fig. 1) generate (a) a set of NRG daddy of polypeptide growth factors— epidermal growth factor (EGF) (Prigent and Lemoine, 1992; isoforms with large differences in the length and compo-