Esrp regulated programs of alternative splicing in skin development and function

描述（由申请人提供）：表皮和皮肤附属物执行基本的屏障功能，保护身体免受环境损害并维持液体电解质平衡。构成皮肤和毛囊的细胞在发育、分化和增殖方面的缺陷会导致许多疾病，如皮肤癌、牛皮癣、大疱性皮肤病和脱发。控制皮肤和毛囊发育的转录程序定义了表皮完整性和头发再生的重要过程。最近，微rna也成为皮肤中基因表达的重要调节因子。相比之下，选择性剪接（AS）在皮肤发育和功能中的作用基本上没有被研究过，没有关于皮肤或其附属物中选择性剪接因子的出版物。上皮-间充质相互作用（EMIs）是表皮和毛囊形成的基础。其中一个重要分支涉及间充质来源的Fgf7和/或Fgf10与成纤维细胞生长因子受体2 Fgfr2-IIIb的上皮特异性剪接异构体的相互作用。Fgf7和Fgf10特异性地与Fgfr2-IIIb相互作用，但不与间质Fgfr2-IIIc相互作用。这种定向信号通路的缺失会导致表皮和毛囊的缺陷。我的实验室发现了上皮特异性剪接因子Esrp1和Esrp2，它们对于Fgfr2-IIIb剪接变体的表达既是必要的，也是充分的

DESCRIPTION (provided by applicant): The epidermis and skin appendages perform essential barrier functions that protect the body from environmental insults and maintain fluid-electrolyte balance. Defects in the development, differentiation, and proliferation of the cells tht comprise the skin and hair follicles lead to numerous diseases such as skin cancer, psoriasis, bullous skin disease, and alopecia. Transcriptional programs that control skin and hair follicle development have defined processes important for epidermal integrity and hair regeneration. More recently microRNAs have also emerged as important regulators of gene expression in the skin. In contrast, the role of alternative splicing (AS) in skin development and function is essentially unstudied~ there have been no publications focused on alternative splicing factors in the skin or its appendages. Reciprocal epithelial- mesenchymal interactions (EMIs) underlie formation of the epidermis and hair follicles. One important arm involves the interaction of mesenchymal derived Fgf7 and/or Fgf10 with an epithelial-specific splice isoform of fibroblast growth factor receptor 2, Fgfr2-IIIb. Fgf7 and Fgf10 specifically interact with Fgfr2-IIIb, but not mesenchymal Fgfr2-IIIc. Abrogation of this directional signaling pathway results in defects in the epidermis and hair follicles. My lab identified the epithelial-specific splicing factors Esrp1 and Esrp2 that are both necessary and sufficient for the expression of the Fgfr2-IIIb splice variant in epithelial cells. We generated Esrp1 and Esrp2 knockout mice and demonstrate that combined Esrp1/Esrp2 KO is lethal and results in epidermal hypoplasia, reduced follicle numbers, and sparse hair. We hypothesize that the Esrps are required for normal epidermal and follicular development and function by enforcing the expression of epithelial-specific splice isoforms. We will determine the phenotypes of Esrp deletion in specific epithelial cell populations in skin and appendages and identify a comprehensive set of Esrp target transcripts through the following Aims: 1) Determine the phenotypes associated with Esrp ablation in the interfollicular epidermis and in hair follicles. We will define phenotypes associated with conditionally ablation of the Esrps in developing and adult epidermis and hair follicles. 2) Define comprehensive programs of Esrp regulated alternative splicing in the epidermis and hair follicle. We will use high throughput sequencing (RNA-Seq) and splicing sensitive microarrays to define genome-wide programs of alternative splicing in the different cell populations that populate the skin. These technologies will be used in conjunction with conditional deletion strategies to define Esrp regulated targets i the epidermis and hair follicle stem cells. The proposed aims constitute the first comprehensive analysis of alternative splicing in skin development and function, thereby introducing a new paradigm to the field. These studies will reveal novel insights into the processes that impact skin development and function.