Role for Lhx genes in skin development and regeneration

皮肤是哺乳动物最大的器官，也是相对容易获得的研究对象。胚胎发育期间器官的发育，以及它们在出生后的维持和再生，都受到信号分子和转录因子的控制，这些蛋白质调节基因的活动。事实上，包括皮肤在内的器官的正常发育和功能受到密切协调的基因表达程序的控制，这些程序调节不同细胞类型特有蛋白质的合成。了解控制皮肤发育的分子机制对于更好地理解器官发育和出生后再生的基本原理非常重要。Lhx转录因子家族是一些器官发育的强大调节者，但它们在皮肤发育中的作用仍然很大程度上尚不清楚。最近发表的一项发现表明，LHX家族的一种蛋白质LHX2参与了上皮干细胞的维持，这激发了人们对描述它们在发育和出生后皮肤中的功能的越来越大的兴趣。上皮干细胞可以产生皮肤表面和皮肤附属物(毛囊、腺体和指甲)细胞，对皮肤的正常发育和维护非常重要。根据我们的初步数据和文献中的数据，我们将进行一项系统的研究，以分析lhx基因参与皮肤发育、出生后生长和再生的机制。具体地说，我们将测试一个假设，即lhx家族不同成员在调节皮肤发育和出生后再生方面的不同作用取决于它们在哪里和何时表达，以及它们在不同类型皮肤细胞中基因活性调节的差异。我们将通过建立LHX2和LHX4在皮肤中的活性被取消或显著增加的模型来解决这一假设。我们将检查这种LHX活性的增加和丢失如何影响皮肤发育、出生后维护和受伤(伤害)后的再生。我们还将确定皮肤细胞中哪些基因受到LHX2和LHX4的调控，以及这种调控的机制是什么。这个项目将帮助我们进一步了解控制皮肤发育和维护的基本机制，并为lhx基因在脊椎动物发育和基因调控中的作用提供新的见解。它还将扩大我们对上皮干细胞的了解，并最终有助于进一步描述控制出生后器官生长和再生的基本机制。该项目还将有助于改善人类健康，并将为目前用于治疗许多皮肤病的方法提供新的见解，包括皮肤癌、慢性上皮伤口和不同形式的脱发。

Skin is the largest organ in mammals and is also relatively accessible for research. Development of organs during embryogenesis, as well as their maintenance and regeneration after birth are controlled by signal molecules and transcription factors, proteins that regulate gene activity. In fact, the proper development and function of organs including skin are controlled by tightly coordinated programmes of gene expression that regulate synthesis of proteins specific for distinct cell types. Understanding the molecular mechanisms controlling skin development is highly important for better understanding the fundamental principles of organ development and postnatal regeneration. The Lhx family of transcription factors are powerful regulators of development of some organs, but their role in skin development remains largely unknown. Increasing interest to delineate their functions in developing and postnatal skin has been stimulated by the recently published discovery demonstrating the involvement of Lhx2, one of the proteins of the Lhx family, in the maintenance of epithelial stem cells. The epithelial stem cells can give rise to skin surface and skin appendage (hair follicles, glands and nails) cells and are important for proper skin development and maintenance. Based on our preliminary data and on data from the literature we will perform a systematic study to analyse mechanisms underlying the involvement of Lhx genes in skin development, postnatal growth and regeneration. Specifically, we will test a hypothesis that different roles of the distinct members of the Lhx family in regulating skin development and postnatal regeneration depends on where and when they are expressed and on their differences in gene activity regulation in distinct types of skin cells. We will address this hypothesis by generating models where activity of Lhx2 and Lhx4 in skin is abolished or significantly increased. We will check how this gain and loss of Lhx activity effect skin development, postnatal maintenance and regeneration after injury (wounding). We will also determine which genes are regulated by Lhx2 and Lhx4 in skin cells and what are the mechanisms of such regulation. This project will help us further understand the fundamental mechanisms controlling skin development and maintenance, as well as providing new insights into the role of Lhx genes in vertebrate development and gene regulation. It will also expand our knowledge about epithelial stem cells and ultimately help in further delineating fundamental mechanisms that govern postnatal organ growth and regeneration. This project will also help in improving human health and will provide new insights into the current approaches used for therapy of many skin disorders including skin cancers, chronic epithelial wounds and distinct forms of hair loss.