MOUSE NUDE LOCUS AND EPIDERMAL DEVELOPMENT

这项研究的目的是为了更好地了解 调节皮肤发育。作为自我更新的结构， 表皮和毛囊需要角质形成细胞之间的平衡 它们的形成和终结的分裂和末端分化 维修。为了深入了解这一过程，申请者是 Winged-Helix Nude(Winged-Helix Nude)的功能研究 小鼠的裸体轨迹和有翼螺旋/叉头的推定成员 转录因子家族。WHN中的功能丧失突变 导致裸体表型，其特征是未能 产生可见的毛发，表皮的异常形成，以及 没有胸腺的。根据他们以前的学习，申请者 构建了一个模型来解释WHN在皮肤形态发生中的作用。 他们发现，当角质形成细胞停止生长时，WHN的表达被诱导 并启动末端分化。他们假设WHN：1) 通过以下方式促进从增殖到分化的转变 激活与分化程序相关的基因；以及2) 诱导分化细胞分泌生长因子。这些增长 然后，因子刺激邻近的角质形成细胞，这些角质形成细胞缺乏WHN 蛋白质，以进行增殖。由于这种旁分泌机制，一个 分化的角质形成细胞在离开增殖期时被替换 以及乘法和差异化之间的平衡 单元格被维护。这项提案的目的是测试这一模型并 为阐明WHN的发病机制提供了一个基本框架 行动。为了评估WHN的直接和旁分泌效应，转基因小鼠 将生成WHN表达式专门针对的对象 角质形成细胞增殖或分化。自.以来 调查人员已获得初步证据，证明WHN刺激 转化生长因子-α的表达与白质形成能力的关系 结合转化生长因子-α启动子并激活转录 已评估。最后，他们和其他人分离出了人类的同源物 WHN，并发现人和小鼠的WHN蛋白有85% 一模一样。作为描述这个同源基因的第一步， 将在正常人和疾病患者中检测WHN的表达模式 皮肤。鉴于小鼠WHN的多效性，人类同源物 他们认为，这可能会在与 过度增殖、脱发或分化异常。

The goal of this research is to gain a better understanding of the regulation of skin development. As self-renewing structures, the epidermis and hair follicles require a balance between keratinocyte cell division and terminal differentiation for their formation and maintenance. To gain insight into this process, the applicants are studying the function of Whn (Winged-helix nude), the product of the mouse nude locus and a putative member of the winged-helix/forkhead family of transcription factors. Loss-of-function mutations in whn result in the nude phenotype, which is characterized by the failure to produce visible hair, the abnormal formation of the epidermis, and the absence of a thymus. Based on their previous studies, the applicants have constructed a model to explain Whn's role in skin morphogenesis. They find that whn expression is induced, as keratinocytes arrest growth and initiate terminal differentiation. They postulate that Whn: 1) promotes the transition from proliferation to differentiation by activating genes associated with the differentiation program; and 2) induces differentiating cells to secrete growth factors. These growth factors then stimulate neighboring keratinocytes, which lack the Whn protein, to proliferate. As a result of this paracrine mechanism, a differentiating keratinocyte is replaced as it leaves the proliferative compartment, and the balance between multiplying and differentiating cells is maintained. The aim of this proposal is to test this model and provide a basic framework for the elucidation of Whn's mechanism of action. To assess Whn's direct and paracrine effects, transgenic mice will be generated in which Whn expression is specifically targeted to either proliferating or differentiating keratinocytes. Since the investigators have acquired preliminary evidence that Whn stimulates the expression of transforming growth factor-a (TGF-a), the ability of Whn to bind to the TGF-a promoter and activate transcription will be evaluated. Lastly, they and others have isolated the human homolog of whn, and find that the human and murine Whn proteins are 85 percent identical. As a first step in the characterization of this homolog, the Whn expression pattern will be examined in normal and diseased human skin. Given the pleiotropic effects of murine whn, the human homolog they believe could play a role in diseases associated with hyperproliferation, hair loss, or aberrant differentiation.