Mouse nude locus and epidermal development

描述(由申请人提供)： 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Foxn1a转录因子家族中翼状螺旋/叉头家族成员的功能。在啮齿动物中，Foxn1功能的丧失导致裸露表型，其特征是皮肤、胸腺和乳腺的形态发生异常。从该项目的工作到目前为止，已经开发了以下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。在上皮内，Foxn1促进了三个基本过程：分化特征的产生，细胞分裂与分化的耦合，以及黑色素的获得。为了调节这些过程，Foxn1激活了细胞间信号系统，从而使上皮细胞之间和黑素细胞之间能够相互协作。因此，根据这个模型，Foxn1作为一个调节环节或纽带，协调皮肤上皮细胞的生长、分化和色素沉着。为了测试这一模型，将确定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Foxn1通路中效应器的功能意义，3)剖析Foxn1调节每个效应器的分子机制。该项目将使用小鼠作为实验系统，利用现有的Foxn1转基因和裸体突变体。在人类中，FOXN1在其序列和功能上是保守的，这表明人类和啮齿动物的蛋白质通过相似的途径发挥作用。因此，通过识别Foxn1的S效应，该项目可能提供与异常色素沉着、过度增殖或异常分化相关的疾病的洞察力。

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 Foxn1a 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, and mammary gland. From the project's work to date, the following model of Foxn1 function has been developed. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. Within the epithelium, Foxn1 then promotes up to three fundamental processes: the production of differentiated features, the coupling of cell division to differentiation, and the acquisition of melanin. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby enabling epithelial cells to cooperate with each other and melanocytes. Thus, according to this model, Foxn1 acts as a regulatory link or nexus, coordinating the growth, differentiation, and pigmentation of cutaneous epithelia. To test this model, the downstream effectors of Foxn1 will be identified. The specific aims of the project are as follows: 1) to isolate and characterize Foxnl effectors, 2) to determine the functional significance of the effectors in the Foxn1 pathway, and 3) to dissect the molecular mechanism by which Foxn1 regulates each effector. The project will use the mouse as an experimental system, taking advantage of existing Foxn1 transgenics as well as nude mutants. In humans, FOXN1 is conserved in its sequence and function, suggesting that the human and rodent proteins act via similar pathways. Thus, by identifying Foxn1's effectors, the project may provide insight into diseases associated with abnormal pigmentation, hyperproliferation, or aberrant differentiation.