A study of schwann cell survival, proliferation and interaction with neurons

The first part of the studies presented in this thesis shows that NDF[beta] (but not NDF[alpha]), a member of a novel family of growth factors, acts as a long-term survival factor for Schwann cell precursors. The potential of NDF[beta] to rescue precursors from apoptotic cell death is independent of activation of either IGF receptors or insulin receptors. In contrast, FGF in the presence of IGF only supports precursor survival for 20 hr. The loss of survival activity of this factor in long-term precursor cultures may be due to the fact that precursors lose their responsiveness to FGF. NDF[beta] not only rescues precursors from apoptotic cell death but also stimulates DNA synthesis in these cells. The mitogenic potential generated by this factor is also independent of both activation of IGF receptors and elevation of cAMP levels. FGF in combination with forskolin, a well known Schwann cell mitogen combination, fails to promote DNA synthesis in Schwann cell precursors. Interestingly, TGF[beta] acts as a mitogen but not survival factor for these cells. Schwann cell precursors cultured in NDF[beta] containing medium not only survive, but also develop into Schwann cells as judged by their ability to survive in defined medium and expression of S100. Furthermore, this study also demonstrates that Schwann cell precursors express the NDF receptors: ErbB2 and ErbB4. The ability of NDF to regulate survival and DNA synthesis in Schwann cell precursors suggests that this molecule may play an important role in the interaction between neurons and precursors. The second part of the thesis shows that both pure neuron conditioned medium and neuronal surface molecules support Schwann cell precursor survival, and neurons, but not Schwann cell precursors, express NDF protein. A soluble ErbB4 protein blocks the survival activity in neuron conditioned medium and that associated with neuronal surfaces, indicating that NDF acts as neuro-glia signalling molecule, mediating precursor survival. Furthermore, the neuronal signals also induce DNA synthesis in Schwann cell precursors and drive the maturation and differentiation of these cells in the neuron-precursor co-cultures. The third part of the thesis demonstrates that two different mitogenic assays may give information that can be related to two different proliferation events, i.e. during nerve development and during Wallerian degeneration. In the first assay, using cells which are assayed immediately after dissociation from nerves, FGF, NDF, TGF[beta] and PDGF have differing mitogenic activities which may reflect the mitogenic activity of these factors in normal nerve. In the second assay, using Schwann cells pre-cultured in serum-containing medium for 5 days, all the factors mentioned above are mitogenic, and the DNA synthesis stimulated by these factors is higher in adult Schwann cells than younger cells, which is in line with the massive proliferation of adult Schwann cells seen in Wallerian degeneration