Genetic Pathways of Hair Medulla Differentiation-Paradigms for Development

描述(申请人提供)：皮肤和头发是明显的外部特征，直接反映个人的健康状况。调节皮肤正常发育和功能的基因通常在其他器官系统中发挥关键作用。虽然人们对皮肤和毛囊的周期和发育有很大的关注，但对毛髓的形成知之甚少。我们最近发现转录调控基因Hoxc13在毛囊分化中起关键作用，包括髓质的形成，它参与控制其他调控基因(Foxq1、Foxn1、JunB)以及结构基因(Crisp1、Krt2-16、Dsc2)。所有这些基因都与毛发以外的组织中的一系列异常有关。我们的总体假设是，使用毛囊髓质作为定义包括这些基因在内的功能调控网络的模型，对于理解涉及相同基因突变或失调的复杂疾病机制将具有重要意义。目的1：我们将首先研究毛发内部缺陷(HID)突变，该突变会影响髓质的形成，并似乎与一种新的基因有关。在最近将HID突变定位到小鼠1号染色体上后，我们将通过高分辨率定位来进一步定位它，以确定相应的基因并表征其表达模式。目的：通过原位杂交和实时定量聚合酶链式反应，交叉检测一组相应的毛髓质突变小鼠的髓质分化相关基因的表达模式，以确定与HID相关的髓质分化的遗传途径。在随后的步骤中，将通过产生复合突变体和体外DMA结合试验来测试单个途径预测。解剖控制毛髓形成的调节回路将有助于理解毛发和皮肤以及许多其他器官系统疾病的潜在机制。

DESCRIPTION (provided by applicant): Skin and hair are obvious external features that directly reflect an individuals' health condition. Genes that regulate normal development and function of the skin often play critical roles in other organ systems. While there is much focus on skin and hair follicle cycling and development, very little is known about the formation of the hair medulla. We recently determined that the transcriptional regulator Hoxc13 plays a key role in hair follicle differentiation, including the formation of the medulla, where it is involved in the control of other regulatory genes (Foxql, Foxnl, Junb), as well as structural genes (Crispl, Krt2-16, Dsc2). All of these genes have been implicated in a host of abnormalities in tissues other than hair. Our overall hypothesis is that using the hair follicle medulla as a model for defining functional regulatory networks including these genes will be of great relevance for understanding complex disease mechanisms involving mutations or dysregulation of the same genes. Aim1: We will begin by investigating the hair interior defect (hid) mutation, which affects medulla formation and appears to be linked to a novel gene. Having mapped the hid mutation recently to mouse chromosome 1, we will localize it further by high-resolution mapping to identify the corresponding gene and characterize its expression pattern. Aim2: To define the genetic pathways of medulla differentiation involving hid, a multi-step approach will utilize cross-examination of expression patterns of genes associated with medulla differentiation in a panel of corresponding hair medulla mutant mice including hid by in situ hybridization j and real-time quantitative PCR. Individual pathway predictions will be tested in subsequent steps by generating compound mutants and in vitro DMA binding assays. Dissecting the regulatory circuitry controlling hair medulla formation will significantly contribute to understanding the mechanisms underlying diseases not only of the hair and skin but of many other organ systems as well.