Proliferation of human Schwann cells induced by neu differentiation factor isoforms

Neu differentiation factor (NDF), a 44-kD polypeptide, is a member of the neuregulin family which also includes glial growth factor, heregulin and acetylcholine-receptor-inducing activity. Previous studies have demonstrated that NDF/glial growth factor/heregulin/acetylcholine-receptor-including activity are products of neurons and mediate proliferation, differentiation and gene expression in Schwann cells of experimental animals. In the present study, the efficacy of different isoforms of NDF in stimulating human Schwann cell proliferation is investigated in Schwann-cell-enriched cultures derived from fetal human dorsal root ganglia (15-20 weeks gestation). NDF isoforms examined include alpha 1, alpha 2, EGF-like domain alpha 2 (EGF alpha 2), alpha 3, beta 1, EGF beta 1, EGF beta, beta 2 and beta 3. For the assessment of Schwann cell proliferation, double immunostaining using antibodies specific for S-100 protein and bromodeoxyuridine was used. While treatment of Schwann cells with NDF alpha isoforms (alpha 1, alpha 2, alpha 3 and EGF alpha 2) had little effect on Schwann cell proliferation, NDF beta isoforms (beta 1, beta 2, beta 3, EGF beta 1 and EGF beta) induced a greatly enhanced proliferation in Schwann cells. The proliferation index in unstimulated Schwann cells was 1.3 +/- 0.9%, whereas in Schwann cells treated with NDF beta isoforms the proliferation index was 21.8 +/- 2.2%. The finding that the truncated beta isoforms such as EGF beta 1 and EGF beta retain a mitogenic activity as potent as full-length beta isoform indicates that the C-terminal portion of the EGF-like domain is responsible for its receptor binding and subsequent biological activity.