Mouse nude locus and skin development

描述(申请人提供)：这项研究的长期目标是更好地了解皮肤发育的调节。本项目的目的是阐明Foxn1的功能，Foxn1是有翼螺旋/叉头转录因子家族的成员。在啮齿动物中，Foxn1功能的丧失导致裸露表型，其特征是皮肤、胸腺、乳腺和指甲的形态发生异常。基于我们到目前为止的工作，我们开发了以下Foxn1函数模型。在皮肤中，当上皮细胞失去增殖和启动末端分化的能力时，它们会诱导Foxn1。然后，Foxn1以一种位置依赖的方式促进多达三个发育过程：宿主细胞的分化，黑素细胞对宿主细胞的黑化，以及周围宿主上皮的生长。为了调节这些过程，Foxn1激活细胞间信号系统，从而诱导上皮细胞相互合作，并诱导色素细胞。因此，根据这个模型，Foxn1作为一个调节网络，协调皮肤组织的生长、分化和色素沉着。为了解释这个Foxn1网络如何工作，我们提出了以下假设：Foxn1通过激活两种类型的细胞外信号将细胞组织成合作单元：扩散信号和细胞结合信号，前者负责Foxn1的S长期行动(例如，诱导细胞增殖和黑素细胞向上皮细胞招募)，后者负责Foxn1的S短期行动(例如，标记上皮细胞以进行着色和锁定色素连接到位)。为了验证这一假设和潜在的模型，将阐明Foxn1的下游效应器。该项目的具体目标如下：1)分离和鉴定Foxn1效应器，2)确定效应器对Foxn1通路和皮肤的意义，3)剖析Foxn1调节其效应器的分子机制。在人类中，FOXN1在序列和功能上是保守的，这表明它使用了一组保守的下游效应器。因此，通过识别Foxn1效应器，该项目应该能够深入了解与黑素细胞和上皮细胞的异常生长、分化或活动相关的疾病。与公共健康相关：这个项目将阐明皮肤发育和再生其保护性上皮特征的基本机制。具体地说，这项工作将描绘一条基因途径，驱动和协调皮肤外部结构的生长、分化和色素沉积。短期内，该项目将部分解释皮肤是如何产生和组装其对环境的屏障的，这将提供基本的保护，防止病原体、危险化学品、紫外线和水分损失。从长远来看，该项目将深入了解皮肤可能是如何在临床上产生或处理的，从而促进更换或修复受损和患病皮肤的方法。

DESCRIPTION (provided by applicant): The long-term objective of this research is to gain a better understanding of the regulation of skin development. The goal of this project is to elucidate the function of Foxn1, a member of the winged- helix/forkhead family of transcription factors. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, mammary gland, and nails. Based on our work to date, we have developed the following model of Foxn1 function. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. In a site- dependent manner, Foxn1 then promotes up to three developmental processes: the differentiation of its host cells, the melanization of its host cells by melanocytes, and the growth of its surrounding host epithelium. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby inducing epithelial cells to cooperate with each other and pigment cells. According to this model therefore, Foxn1 acts as a regulatory nexus, coordinating the growth, differentiation, and pigmentation of cutaneous tissues. To explain how this Foxn1 nexus works, we have developed the following hypothesis: that Foxn1 organizes cells into cooperative units by activating two types of extracellular signals - diffusible signals, which are responsible for Foxn1's long-range actions (e.g., the induction of cell proliferation and the recruitment of melanocytes to epithelial cells), and cell-bound signals, which are responsible for Foxn1's short-range actions (e.g., the flagging of epithelial cells for pigmentation and the locking of pigmentary connections into place). To test this hypothesis and the underlying model, the downstream effectors of Foxn1 will be elucidated. The specific aims of the project are as follows: 1) to isolate and characterize Foxn1 effectors, 2) to determine the significance of the effectors to the Foxn1 pathway and skin, and 3) to dissect the molecular mechanisms by which Foxn1 regulates its effectors. In humans, FOXN1 is conserved in sequence and function, suggesting it employs a conserved set of downstream effectors. Thus, by identifying Foxn1 effectors, the project should provide insight into disorders associated with the abnormal growth, differentiation, or activity of melanocytes and epithelial cells. PUBLIC HEALTH RELEVANCE: This project will elucidate fundamental mechanisms by which the skin develops and regenerates its protective epithelial traits. Specifically, the work will delineate a genetic pathway that drives and coordinates the growth, differentiation, and pigmentation of the skin's external structures. In the short term, the project will explain in part how the skin produces and assembles its barrier to the environment, which provides essential protection against pathogens, hazardous chemicals, ultraviolet light, and water loss. Over the long term, the project will provide insight into how skin may be clinically generated or manipulated, thus facilitating methods for the replacement or repair of damaged and diseased skin.