Genetic Control of Epidermal Appendage Development

描述：(逐字)每年每2000名婴儿中就有1名出生时皮肤严重 或皮肤附件缺陷，以及更多的人被诊断为皮肤异常 生命的前六个月。这些缺陷中的许多是由基因突变引起的 调节精心设计的双向信令所需的 胚胎真皮和表皮之间的级联是正常所必需的 皮肤发育。我们的数据表明，人类之间复杂的相互作用 调控基因Engraed-(en-1)、Wnt7a和Lmxlb对正常至关重要 指甲和分泌腺发育。更具体地说，埃尼似乎在发挥作用 在附肢发育的三个阶段：图案化、形态发生和 差异化。我们建议： 1.为我们的突变研究提供基础，描绘出正常的 小汗腺和指甲的形态发生和细胞分化的步骤 无论是形态标准还是分子标准。 2.确定小汗腺对EN_1、WNT_7a和LMX_1b的需要量 和指甲发育通过表征形态和标记的变化 发生在单功能丧失和双功能丧失的基因表达模式 变种人。 3.确定在发展的哪些阶段需要EN1来促进 内分泌腺的形成和抑制异位甲样分化 不同发育阶段En-I基因功能的去除 条件性EN-1突变等位基因。 4.确定外胚层表达的EN1是否足以指导 外用抑制指甲/毛发发育的作用 利用逆转录病毒载体表达EN-1。

DESCRIPTION: (Verbatim) Each year 1/2,000 infants is born with a serious skin or skin appendage defect and many more are diagnosed with skin anomalies in the first six months of life. Many of these defects result from mutations in genes required for regulating the carefully choreographed, bi-directional signaling cascades between embryonic dermis and epidermis that is necessary for normal skin development. Our data indicate that complex interactions between the regulatory genes Engrailed- (En 1), Wnt7a and Lmxlb are critical for normal nail and eccrine gland development. More specifically, Eni appears to function at three stages of appendage development: patterning, morphogenesis and differentiation. We propose to: 1. To provide a foundation for our mutant studies by delineating the normal steps of eccrine gland and nail morphogenesis and cytodifferentiation using both morphological and molecular criteria. 2. To determine the requirements for En 1, Wnt7a and Lmx lb in eccrine gland and nail development by characterizing the alterations in morphology and marker gene expression patterns that occur in single and double loss-of-function mutants. 3. To determine at what stages in development En1 is required to promote eccrine gland formation and inhibit ectopic nail-like differentiation by abrogating En I gene function at different developmental stages using a conditional En 1 mutant allele. 4. To determine whether ectodermally expressed En1 is sufficient to direct eccrine gland development and to inhibit nail/hair development by ectopically expressing En 1 using retroviral vectors.