Role for Lhx genes in skin development and regeneration

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.

The Lhx family of transcriptional regulators are powerful regulators of ectodermal development, although their role in skin development remains largely unknown. Increasing interest to delineating their functions in developing and postnatal skin has been stimulated by the recently published discovery demonstrating the involvement of the Lhx2 in maintenance of the epithelial stem cells. 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 differential activity of the distinct members of the Lhx family in regulating skin development and postnatal regeneration depends on spatial and temporal specificity of their expression and on differential activation of their targets in distinct types of skin cells. To address this hypothesis, we will first define the effects of the gain or loss of Lhx2 and Lhx4 activity on skin development and postnatal growth by using transgenic and/or knockout mice as models. In particular, we will generate transgenic mice overexpressing Lhx2 or Lhx4 (promoter: K14) and will analyse the phenotype of the skin of Lhx2 or Lhx4 knockout mice or double Lhx2/4 null mice after transplantation onto nude mice. Next we will delineate the roles for Lhx2 and Lhx4 in controlling postnatal skin regeneration. We will analyse the dynamics of the wound healing process and stem cells in genetically engineered mice with gain or loss of Lhx2/4 activity. Finally, we will identify transcriptional targets for Lhx2 and Lhx4 that mediate cross-talk with other molecular pathways regulating skin development, growth and regeneration. Taken together, these data will provide new knowledge into the fundamental mechanisms that control skin development and will bring new insights into the understanding of the role for epithelial stem cells in postnatal skin regeneration and growth.