Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2.

Abstract

The ability of sensory axons to stimulate Schwann cell proliferation by contact was established in the 1970s. Although the mitogen responsible for this proliferation has been localized to the axon surface and biochemically characterized, it has yet to be identified. Recently a family of proteins known as heregulins (HRGs) has been isolated, characterized, and shown to interact with a number of class 1 receptor tyrosine kinases, including the erbB2, erbB3, and erbB4 gene products. These factors include glial growth factor, a Schwann cell mitogen. We The phenomenon of Schwann cell (SC) proliferation driven by axonal contact was demonstrated nearly 20 years ago by in vitro observations using both rat (1) and chick (2) tissues. Characterization of this mitogenic activity has shown it to be associated with the surface of the axon and to be sensitive to trypsin, heat, and glutaraldehyde treatment, indicating the involvement of a protein component (3). This protein is salt extractable, indicating that it is peripherally, rather than integrally, membrane bound (4). Mitogenic activity can be detected in the solubilized fraction (130,000 x g, 1 hr) of the extract, and can be inhibited by low concentrations (half-maximally at 0.5-0.7 jig/ml) of heparin (4). Further, treatment of axons with heparatinase removes the mitogenic activity from the axon (5). These results indicate that the axonal mitogen is a protein or protein-proteoglycan complex peripherally associated with the axonal membrane (see ref. 6 for review).The primary sequence for one of the best-characterized SC mitogens, glial growth factor (GGF), has been elucidated and expression plasmids containing the appropriate cDNA have allowed the production of these purified factors (7). Sequence analysis has shown that GGF is a member of a family of proteins which include GGF II (7), acetylcholine receptorinducing activity (ARIA) (8), Neu differentiation factorThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.(NDF) (9), and heregulin (HRG) a and ,B (see refs. 10 and 11 for review). Chemical crosslinking experiments (12) have shown HRG to interact with pl85erbB2. These proteins have also been shown to stimulate the phosphorylation of a number of class 1 receptor tyrosine kinases, including those encoded by erbB2, erbB3, and erbB4 (7,10,(12)(13)(14).Studies by us (15) and by others (16) have shown other members of the HRG family (NDF, HRG,B1) to be effective mitogens for SCs. The stimulation of human SC proliferation by purified, soluble recombinant HRG can be blocked by a monoclonal antibody raised against the p185erbB2 receptor (2C4) (15).Our recent observations on human SC proliferation have shown that rat sensory neurons are mitogenic for human SCs. In this study we have cocultured human (and rat) adult-derived SCs with purified rat sensory neurons in the presence or absence of antibodies against pl85er...

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…For example, the common transmembrane topology of mesenchymal isoforms, which is not shared by most neuronal factors, may enhance binding and increase availability of the lower a nity ligands. This proposition is supported by the apparent short range of NDF/neuregulin action in vivo, including its involvement in cardiac development (Gassmann et al, 1995;Lee et al, 1995;Meyer and Birchmeier, 1995), contact-induced mitosis of Schwann cells by neuron-expressed neuregulins (Morrissey et al, 1995), co-localization of neuregulin and its receptors in the neuromuscular synapse (Zhu et al, 1995), and mesenchyme-epithelia interaction during mammary gland development (Yang et al, 1995).…”

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…The Nrg1 signal that drives Schwann cell development is provided by neurons, and presented in the axolemma. Thus, axonal membranes are mitogenic for Schwann cell precursors, and the mitogenic agent is Nrg1 (Dong et al, 1995;Morrissey et al, 1995;Schroering and Carey, 1998). Genetic evidence demonstrates that type III Nrg1 drives Schwann cell development (Meyer et al, 1997); this isoform can remain membrane-bound after proteolytic cleavage (Cabedo et al, 2002).…”

Development of the Schwann cell lineage: From the neural crest to the myelinated nerve

“…Transection of sciatic nerves in newborn rats results in a reduction in Schwann cell proliferation as they lose contact with the axons (Komiyama and Suzuki, 1992), consistent with the idea that axons provide a mitogenic signal for developing Schwann cells. One of the axonal mitogenic factors has been shown to be NRG1, in in vitro Schwann cell-DRG co-culture studies (Morrissey et al, 1995), although there appears to be no direct in vivo evidence for this yet.…”