Functional analysis of Trps1 in skin and hair follicle development.

摘要

Hair follicle morphogenesis involves a series of reciprocal epithelial-mesenchymal interactions that drive the growth and differentiation of the developing follicle. The goal of this thesis was to address the question of how a simple epithelium and underlying mesenchyme interact to generate the diverse cell types of the hair follicle. My thesis focused on identifying novel transcriptional regulators of hair follicle morphogenesis and characterizing the expression and function of such molecules in both mice and humans.I initially used microarray hybridization analysis to generate a global transcriptional profile of murine skin and hair follicle morphogenesis. Through separate examination of the epithelial and mesenchymal compartments, we identified novel secreted and membrane-bound factors regulating either epidermal placode formation, including members of the stratified epithelium secreted peptides complex, the Wnt inhibitor Dickkopf 4 and the potential Hoxa13 target Derp7, or the reciprocal condensation of the underlying dermis, such as Syndecan-1 and members of the epidermal and keratinocyte growth factor families.To further refine the signaling molecules that coordinately control the regulation of both compartments, I focused on the zinc-finger transcription factor Trps1. I demonstrated that Trps1 localizes to the nuclei of dermal papillae cells and the highly proliferative epithelial cells of anagen hair follicles, indicating a role for Trps1 in promoting growth of the follicle.To identify downstream target genes of Trps1, I performed microarray hybridization analysis comparing expression patterns in wild-type versus Trps1Deltagt/Deltagt embryonic whisker pads. I established that Trps1 directly activates a number of secreted Wnt antagonists and transcription factors in the vibrissa follicle, including the hair follicle stem cell regulators Lhx2 and Sox9. Upon analysis of the vibrissa follicle defects in Trps1Deltagt/Deltagt embryos, I uncovered a transcriptional hierarchy including Trps1, Shh and Sox9 that controls the specification of early hair follicle progenitors and their subsequent proliferation.Finally, I used comparative genomics and morphological analyses to characterize a position effect on TRPS1 associated with hypertrichosis in both humans and mice. I demonstrated that TRPS1 is subject to complex tissue- and temporal-specific regulation, as underexpression of the gene can result in both hypotrichosis and hypertrichosis, underscoring its critical role in hair follicle development.