Mechanisms of signal transmission in vertebrate skin appendage development.

项目摘要/摘要 皮肤附属物，包括牙齿、毛发、分泌物和乳腺，很明显，在医学上是不重要的。 人的体表的一些特征。先天性和获得性皮肤附属器疾病是常见的 以及经常使人虚弱的条件。尽管人类基因分析和临床皮肤病学有关联。 与皮肤附件疾病相关的多个基因座，将遗传损害与人类联系起来的分子病因学 在许多情况下，表型仍然不清楚。了解调节皮肤AP的分子机制 实验模型系统中的悬垂图案和形态发生为发展提供了新的途径 皮肤病的治疗方法。事实上，对鸡和老鼠模型系统的研究极大地促进了我们的 对皮肤附属物发育的遗传规律的了解并已影响临床 皮肤科。重要的是，构图线索、形态发生细胞行为和调控机制 连接它们在斑马fish皮肤附属物的发育过程中是保守的。因为皮肤附属物形成了超级fi- 在发育中的fish透明皮肤中，研究斑马fish皮肤的纹饰和形态发生使 细胞和分子动力学的活体分析，其分辨率目前在其他模型系统中是不可能的。 目标1的研究将有助于我们理解皮肤附属物的正确分布是如何 通过利用活体成像和条件遗传学来测试一个新的迁徙种群的作用 真皮细胞可能调节皮肤附属物的图案。这些研究还将首次揭示， 控制完整脊椎动物皮肤真皮细胞迁移的分子机制。目标2中的研究将阐明- 调控信号蛋白动态空间分布的日期机制是已知的 人类早期皮肤附属物形态发生过程中的上皮-间充质相互作用。通过使用条件- 转基因表达重建遗传性外胚层斑马fi-sh模型中的信号网络 不典型增生，这些实验将揭示上皮-间充质信号相互作用的机制 在分子分辨率下。总之，这些研究将解决一些最重要的悬而未决的问题 关于皮肤附属物的发育，并为理解分子病因学提供了潜在的途径 影响这些组织的人类疾病。 1

PROJECT SUMMARY/ABSTRACT Skin appendages, including teeth, hair, eccrine and mammary glands, are conspicuous and medically impor- tant features of the human integument. Congenital and acquired disorders of skin appendages are common and frequently debilitating conditions. Although human genetic analyses and clinical dermatology have associ- ated numerous loci with skin appendage disorders, the molecular etiologies linking genetic lesions to human phenotypes in many cases remain obscure. Understanding molecular mechanisms that regulate skin ap- pendage patterning and morphogenesis in experimental model systems provides new avenues for developing therapies for skin disease. Indeed, research on chicken and mouse model systems has greatly advanced our understanding of the genetic regulation of skin appendage development and has already impacted clinical dermatology. Importantly, patterning cues, morphogenetic cell behaviors and the regulatory mechanisms that link them are conserved in zebrafish skin appendage development. Because skin appendages form superficial- ly in the transparent skin of developing fish, studying zebrafish skin patterning and morphogenesis enables in vivo analysis of cellular and molecular dynamics at resolutions not currently possible in other model systems. Studies in Aim 1 will contribute to our understanding of how the correct distribution of skin appendages is achieved by leveraging live imaging and conditional genetics to test the role of a novel population of migratory dermal cells likely to regulate skin appendage patterning. These studies will also uncover, for the first time, molecular mechanisms that govern dermal cell migration in intact vertebrate skin. Studies in Aim 2 will eluci- date mechanisms regulating the dynamic spatial distribution of signaling proteins known to be necessary for epithelial–mesenchymal interactions during early skin appendage morphogenesis in humans. By using condi- tional transgene expression to re-construct signaling networks in a zebrafish model of hereditary ectodermal dysplasia, these experiments will reveal mechanisms governing epithelial–mesenchymal signaling interactions at molecular resolution. Together, these studies will address some of the most important unanswered questions regarding skin appendage development and provide potential inroads to understanding the molecular etiology of human disorders affecting these tissues. 1