Lef1 Target Genes Regulating Hair Follicle Morphogenesis and Differentiation

Inductive signaling between epithelial and mesenchymal compartments during embryogenesis is an early and central event in the formation of skin appendages such as hair follicles. Importantly, the aberrant usage of these signaling events can lead to the development of tumors throughout life. The Wnt signaling pathway and members of the Lef/Tcf transcription factor family are key regulators of hair follicle development. Gene targeting studies have shown that mice deficient for Lymphoid enhancer factor 1 (Lef1) fail to form most hair follicle types, suggesting involvement in the initial steps of hair follicle morphogenesis. Indeed, constitutive activation of Wnt signaling in transgenic mice led to de novo hair follicle formation in postnatal epidermis, a process normally restricted to embryonic skin. Furthermore, hair tumors developed in these mice, underscoring the role of this signaling pathway in both hair cell fate determination and skin tumorigenesis. The aim of this proposal is to identify novel Lef1 target genes required for hair follicle morphogenesis. The total pool of genes expressed in Lef1 knockout and wildtype skin will be compared by microarray analysis to allow identification of early skin epithelial genes that are not transcribed when Lef1 is missing. Candidate target genes will be screened and their Lef1 dependent regulation will be analyzed using Lef1 expressing matrix cells, specifically isolated from transgenic reporter mice. Once characterized, their functions will be determined in vivo, using knockout and transgenic approaches. Elucidating the molecular mechanisms leading to hair formation will not only enhance our understanding of the basic principles involved in cell fate determination, but may also provide new insights into the pathogenesis of skin neoplasms.