Genetic Pathways of Hair Medulla Differentiation-Paradigms for Development

描述（由申请人提供）：皮肤和头发是直接反映个人健康状况的明显外部特征。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。虽然人们非常关注皮肤和毛囊的循环和发育，但对头发髓质的形成却知之甚少。我们最近确定转录调节因子Hoxc13在毛囊分化中起关键作用，包括髓质的形成，在那里它参与控制其他调节基因（Foxql, Foxnl, Junb），以及结构基因（Crispl, Krt2-16, Dsc2）。所有这些基因都与除头发以外的许多组织异常有关。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节网络的模型，将对理解涉及相同基因突变或失调的复杂疾病机制具有重要意义。目的1：我们将从研究毛发内部缺陷（hid）突变开始，它影响髓质形成，似乎与一种新的基因有关。在最近将该突变定位到小鼠1号染色体后，我们将通过高分辨率定位进一步确定相应的基因并表征其表达模式。目的2：为了确定涉及hid的髓质分化的遗传途径，一种多步骤的方法将利用原位杂交和实时定量PCR对包括hid在内的相应毛髓质突变小鼠的髓质分化相关基因的表达模式进行交叉检验。个体途径预测将在随后的步骤中通过生成复合突变体和体外DMA结合试验进行测试。解剖控制头发髓质形成的调节电路将大大有助于理解疾病的机制，不仅是头发和皮肤，还有许多其他器官系统。

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.