Transcriptional Regulation of Melanocyte Development

描述(申请人提供)：本申请的长期目标是了解转录因子是如何控制发育的 脊椎动物中神经脊源性色素细胞或黑素细胞的 胚胎。通过在核水平上发挥作用并与特定的DNA结合 基因启动子或增强子区域上的元件，转录因子 与基本转录机制相互作用以激活或 抑制转录。全套基因的转录可能会受到影响 通过单个转录因子的作用，导致激活 或抑制有能力决定主要疾病的基因程序 发育中的细胞的特征。基因和生化数据来自 成熟的小鼠被毛颜色突变和来自先天性 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，黑素细胞不是 不仅赋予皮肤和头发色素，而且还促进适当的 眼睛和内耳的发育也是如此。这样做的具体目的是 建议了解转录因子MITF和 Pax3在黑素细胞发育中的作用 黑素细胞前体细胞中碱性螺旋-环-螺旋转录因子影响 黑素细胞的发育和分化。实现这些目标，使用 转基因动物与神经原代培养技术的结合 CREST细胞，以及基因表达分析的分子方法，将增强 在这一领域进行的先前工作的发现，将有助于 阐明已知的转录因子对 黑素细胞系在发育过程中的功能发育。他们 也将有助于确定已知的扰乱黑素细胞发育的因素 而差异化扮演着这一角色。这些实验的结果具有 可能有助于我们理解某些基因的病因学 色素沉着障碍，正常色素沉着的调节，以及 增生性黑素细胞皮损的发生有实质性的发病率，例如 巨大的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.