Proliferation of human Schwann cells induced by neu differentiation factorisoforms

Neu differentiation factor (NDF), a 44-kD polypeptide, is a member of the n euregulin family which also includes glial growth factor, heregulin and ace tylcholine-receptor-inducing activity. Previous studies have demonstrated t hat NDF/glial growth factor/heregulin/acetylcholine-receptor-including acti vity are products of neurons and mediate proliferation, differentiation and gene expression in Schwann cells of experimental animals. In the present s tudy, the efficacy of different isoforms of NDF in stimulating human Schwan n cell proliferation is investigated in Schwann-cell-enriched cultures deri ved from fetal human dorsal root ganglia (15-20 weeks gestation). NDF isofo rms 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 assess ment 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 isoform s (beta 1, beta 2, beta 3, EGF beta 1 and EGF beta) induced a greatly enhan ced 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 t he truncated beta isoforms such as EGF beta 1 and EGF beta retain a mitogen ic activity as potent as full-length beta isoform indicates that the C-term inal portion of the EGF-like domain is responsible for its receptor binding and subsequent biological activity.