The long-term goal of this research program is to understand how extracellular signals guide select cells within a multipotent epithelial sheet to choose a cell fate and develop into a bud structure during organogenesis. Upon the synthesis of published reports and previous work, the specific hypothesis of this proposal is that the transcription factor Snail affects both the genetic program and architectural characteristics of the cell to promote the formation of this bud. Using mammalian hair follicle development as a model system, the contribution of Snail to bud morphogenesis will be studied by: 1. Identifying the effects of Snail expression. The function of Snail in budding morphogenesis will be studied by (i) Engineering an inducible-conditional knockout of Snail to establish its physiological importance in hair development; (ii) Applying microarray technology to identify targets of this transcription factor with a focus on genes that may explain Snail's ability to affect cell growth and specification; (ii) Investigating the role of Snail in the remodeling of the basement membrane. 2. Investigating the mechanisms regulating Snail expression. The multi-tiered regulation of Snail will focus on the hypothesis that RhoB modulates TGFbeta2-dependent activation of the Snail promoter and that GSK33 and MARK govern the half-life and subcellular localization of this transcription factor. Since the formation of a bud structure is a common theme in the development of a variety of organs, the knowledge gained from these studies with the hair will shed light on the development and regeneration of other parts of the mammalian body. Moreover, Snail and the processes it affects are often aberrant during cancer so an understanding of how this protein is regulated and how it affects cellular behavior will provide new insights into potential routes of therapeutic intervention. ? ? ?
