SCHWANN-CELLS EXPRESS NDF AND SMDF N-ARIA MESSENGER-RNAS, SECRETE NEUREGULIN, AND SHOW CONSTITUTIVE ACTIVATION OF ERBB3 RECEPTORS - EVIDENCE FOR A NEUREGULIN AUTOCRINE LOOP/

Cultured Schwann cells secreted low levels (30 pg/ml/1.5 x 10(6) cells ) of a 45-kDa neuregulin protein and showed constitutive activation of a neuregulin receptors, Erb-B3, suggesting the existence of an autocr ine loop involving neuregulins in Schwann cells. RT-PCR analyses indic ated that Schwann cells and fibroblasts in culture produced SMDF/n-ARI A and NDF but not GGF neuregulin messages. Schwann cell and fibroblast neuregulin messages encoded both beta and alpha domains; Schwann cell transcripts encoded only transmembrane neuregulin forms while fibrobl ast messages encoded transmembrane and secreted forms. SMDF/n-ARIA and NDF messages were also expressed in early postnatal rat sciatic nerve , suggesting a role for neuregulins in peripheral nerve development. A n anti-neuregulin antibody inhibited the mitogenic response of Schwann cells to cultured neurons and to extracts of cultured neurons or embr yonic brain, consistent with the accepted paracrine role of neuregulin s on Schwann cells. Surprisingly, the same antibody inhibited Schwann cell proliferation stimulated by several unrelated mitogens including bFGF, HGF, and TGF-beta 1. These data implicate both paracrine and aut ocrine pathways involving neuregulin form(s) in Schwann cell mitogenic responses. (C) 1997 Academic Press.