EXPRESSION OF NEUREGULINS AND THEIR PUTATIVE RECEPTORS, ERBB2 AND ERBB3, IS INDUCED DURING WALLERIAN DEGENERATION

Schwann cell dedifferentiation and proliferation is a prerequisite to axonal regeneration in the injured peripheral nervous system. The neur egulin (NRG) family of growth and differentiation factors may play a p articularly important role in this process, because these axon-associa ted molecules are potent Schwann cell mitogens and differentiation fac tors in vitro. We have examined Schwann cell DNA synthesis and the exp ression of NRGs and their receptors, the erbB membrane tyrosine kinase s, in rat sciatic nerve, sensory ganglia, and spinal cord 0-30 d posta xotomy. Analysis of NRG cDNAs from these tissues revealed several nove l splice variants and showed that cells endogenous to injured nerve ex press NRG mRNAs. A selective induction of mRNAs encoding the glial gro wth factor (GGF) subfamily of NRGs occurs in nerve beginning 3 d posta xotomy and thus coincides with the onset of Schwann cell DNA synthesis . In later stages of Wallerian degeneration, however, Schwann cell mit ogenesis markedly decreases, whereas elevated GGF expression persists. Of the four known erbB kinases, Schwann cells express both erbB2 and erbB3 receptors over the entire interval studied. Expression of erbB2 and erbB3 is coordinately induced in response to axotomy, indicating t hat Schwann cell responses to NRGs may be modulated by changes in rece ptor density. Neuregulin (including transmembrane precursors) and erbB protein are associated with Schwann cells postaxotomy. Thus, in contr ast to the concept of NRGs as axon-associated mitogens, our findings s uggest that NRGs produced by Schwann cells themselves may be partially responsible for Schwann cell proliferation during Wallerian degenerat ion, probably acting via autocrine or paracrine mechanisms.