Transcriptional Regulation of Melanocyte Development

描述（由申请人提供）：本项目的长期目标 应用是为了了解转录因子如何控制发育， 脊椎动物的神经嵴来源的色素细胞，或黑色素细胞， 胚胎通过在细胞核水平上作用并与特定的DNA结合 基因的启动子或增强子区域上的元件，转录因子具有 与基础转录机制相互作用以激活或 抑制转录。整个基因组的转录都可能受到 通过单个转录因子的作用， 或抑制基因程序，有能力决定主要的 细胞发育的特征。基因和生化数据来自 明确的小鼠毛色突变体和先天性 色素沉着障碍都支持转录的重要作用 促进黑素细胞正常发育的因素，黑素细胞是一种不 不仅赋予色素的皮肤和头发，但也促进了适当的 眼睛和内耳的发育。具体目标是 建议是了解转录因子Mitf和 Pax 3在黑素细胞发育中的作用，并确定 黑素细胞前体中碱性螺旋-环-螺旋转录因子影响 黑素细胞的发育和分化。为了实现这些目标， 与转基因动物技术相结合，神经细胞的原代培养 嵴细胞和基因表达分析的分子方法，将增强 从以前的工作中已经在这一领域进行的调查结果，将有助于 阐明转录因子的机制，已知转录因子对 黑素细胞谱系功能在发育过程中的发育。他们 也将有助于确定已知干扰黑素细胞发育的因素 和分化在这个角色中起作用。这些实验的结果具有 可能有助于我们理解某些遗传性疾病的病因， 色素沉着障碍，正常色素沉着的调节，以及 增生性黑色素细胞病变的发生， 大先天性黑色素细胞痣和恶性黑色素瘤。

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand how transcription factors control the development of neural crest-derived pigment cells, or melanocytes, in the vertebrate embryo. By acting at the level of the nucleus and binding to defined DNA elements on promoter or enhancer regions of genes, transcription factors have the ability to interact with the basal transcriptional machinery to activate or repress transcription. Transcription of entire sets of genes can be influenced by the actions of individual transcription factors, leading to the activation or repression of gene programs that have the ability to determine major characteristics of a developing cell. Genetic and biochemical data from well-established murine coat color mutants and from patients with congenital disorders of pigmentation all support the important role of transcription factors in promoting the proper development of the melanocyte, a cell which not only confers pigment to the skin and hair, but also promotes the proper development of the eye and inner ear as well. The specific aims of this proposal are to understand the function of the transcription factors Mitf and Pax3 in melanocyte development and to determine how the misexpression of a basic helix-loop-helix transcription factor in melanocyte precursors affects both melanocyte development and differentiation. Achieving these aims, using a combination of techniques with transgenic animals, primary cultures of neural crest cells, and molecular methods of gene expression analysis, will enhance findings from previous work that has been performed in this field and will help elucidate the mechanisms whereby transcription factors known to be crucial to the development of the melanocytic lineage function during development. They will also help determine how factors known to perturb melanocyte development and differentiation act in this role. The results of these experiments have the potential to contribute to our understanding of the etiology of certain genetic disorders of pigmentation, the regulation of normal pigmentation, and the genesis of proliferative melanocytic lesions with substantial morbidity such as large congenital melanocytic nevi and malignant melanoma.