Von Recklinghausen Neurofibromatosis (NF) is a human genetic disorder characterized by the presence of multiple neurofibromas and pigmented spots on the skin. It has been suggested that the neural crest-derived Schwann cells in NF patients have somehow become unstable in their phenotype, resulting in their neoplastic growth (to form the neurofibromas) and metaplastic transformation into melanocytes (to form the pigmented spots). In previous work, we found that phorbol ester treatment of Schwann cell precursors of avian embryos caused these cells to behave like human NF cells--i.e., these cells became more invasive and underwent a metaplastic transformation into melanocytes. More recently, we found that decreased levels of protein kinase C in these avian Schwann cell precursors may be responsible for mediating these effects of phorbol ester treatment. Our findings may also suggest that alterations in the protein kinase C-related second messenger system in Schwann cells of NF patients may be responsible for some of the systems of this disorder. The overall aim of this proposal is, therefore, to test further the hypothesis that control of endogenous protein kinase C (pkC) levels in neural crest (NC) cells if responsible for various differentiative and migratory properties of these early embryonic cells. Specifically, we wish to test the notion that low levels of pkC permit the further migration of NC cells and cause the commitment of a NC subpopulation to the melanocyte lineage. We also wish to test whether relatively higher levels for pkC cause NC cells to stop migrating and commit to the Schwann cell lineage. An important corollary to this hypothesis is the possibility that growth factors of the epidermal growth factor (EGF) family may normally affect pkC levels in NC cells, and thereby, influence the differentiation and migration of NC cells. We will determine whether evoked changes in pkC levels influence the differentiation and migration of NC cells in vivo and in culture, and whether these changes are due to regulation at the transcriptional, translational, or post-translational levels. We will also test whether various growth factors are normally involved in the regulation of NC development. If these studies indicate that pkC is involved in the process by which the Schwann cell phenotype is stabilized, this would suggest a possible molecular mechanism for some of the symptoms of NF, and would provide an experimental model system for further studies of this disorder.
