Regulation of Melanocyte Development and Differentiation

使用I型神经纤维瘤病的小鼠模型，描述我们关于神经纤维蛋白调节黑素细胞发育和分化的工作的手稿，目前正在为《细胞科学》杂志进行轻微修订。这项研究的结果表明，在黑素细胞发育过程中，神经纤维蛋白负向调节Kit-MITF信号轴。他们还将神经纤维素确立为色素沉着的重要调节因素。尽管我们发现，与永生化的黑素细胞相比，抑制MAP激酶级联对原代黑素细胞中色素酶基因的表达具有相反的影响，但对神经纤维蛋白缺失的反应是相似的，这表明它在调节色素沉着的MAP激酶信号通路的扰动中占主导地位。我们的结果有助于解释在I型神经纤维瘤病患者中观察到的色素沉着损害的分子基础。描述我们在瓦登堡综合征小鼠模型中黑素细胞发育和存活的工作的手稿目前正在提交过程中。在这项研究中，研究了血管纹中的黑素细胞，这是内耳的一层，其适当的功能依赖于黑素细胞的存活。我们发现，干细胞因子/Kit配体和多肽ET-3的结合可以挽救转录因子MITF缺陷的工业黑素细胞的存活。这些结果有助于解释在遗传性发育性色素障碍Waardenburg综合征和Tietz综合征患者中观察到的严重的耳部色素表型和相对轻微的皮肤色素表型之间的重要差异。与该项目主题相关的其他合作工作也旨在进一步了解MITF转录在减轻黑素细胞对紫外线照射的凋亡反应中的作用。

The manuscript describing our work on the regulation of melanocyte development and differentiation by neurofibromin, using a mouse model of type I neurofibromatosis, is currently under minor revision for the Journal of Cell Science. 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. The manuscript describing our work on melanocyte development and survival in a mouse model of Waardenburg syndrome is currently in the submission process. 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. Additional collaborative work associated with the theme of this project also is designed to understand further the role of the Mitf transcription in mitigating the apoptotic response of melanocytes to ultraviolet irradiation.