We published a manuscript describing our work on the regulation of melanocyte development and differentiation by neurofibromin, using a mouse model of type I neurofibromatosis, in the Journal of Cell Science earlier this year. The results of this study showed that neurofibromin negatively regulates the Kit - Mitf signaling axis during melanocyte development. They also establish neurofibromin as an important regulator of pigmentation. Despite the fact that we showed that inhibition of the MAP kinase cascade has opposing effects upon the expression of pigmentary enzyme genes in primary melanocytes compared to immortalized melanocytes, the response to loss of neurofibromin is comparable, suggesting that it is dominant to perturbations of the MAP kinase signaling pathway in regulating pigmentation. Our results help to explain the molecular basis of the hyperpigmented lesions observed in patients with type I neurofibromatosis. We are completing work on melanocyte development and survival in a mouse model of Waardenburg syndrome following feedback from a journal submission earlier this year. In this study, melanocytes in the stria vascularis, a layer of the inner ear whose proper function is dependent upon melanocyte survival, were studied. We found that the survival of strial melanocytes deficient in the transcription factor Mitf could be rescued by the combination of stem cell factor/Kit ligand and the peptide endothelin-3. These results help to explain an important disparity between the severe otic pigmentary phenotype and the relatively mild cutaneous pigmentary phenotypes observed in individuals with the inherited developmental pigmentary disorders Waardenburg syndrome and Tietz syndrome. A manuscript is being prepared in a collaboration designed to understand further the role of the Mitf transcription in mitigating the apoptotic response of melanocytes to ultraviolet (UV) irradiation.
