This proposal aims at understanding the molecular mechanisms underlying the developmental choices made during hair follicle morphogenesis, a process influenced by a number of putative factors, including transcription factors, cell adhesion molecules, and growth factors. Previous studies have suggested LEF-1 as the best candidate for a global regulator of hair development. Whole mount in situ hybridizations on embryos of wildtype and LEF-1 knockout mice will be performed to test which known factors are involved in the LEF-1 pathway. Transgenic mice expressing a LEF-1 promoter-lacZ chimeric gene will be made to verify the utility of the LEF-1 promoter, to assess the relative importance of upstream factors in LEF-1 regulation, and to develop a useful agent in making an expression vector to target desired genes to the hair follicle. To further explore the function of P-cadherin, a possible downstream target of LEF-1, two types of transgenic mice will be generated: a) expressing a LEF-1 promoter driving a dominant negative form of P- cadherin (to study its effect on both hair morphogenesis and cell adhesion, and to unveil the molecular links between the two processes); b) expressing a P-cadherin promoter with wildtype or mutated LEF-1 sites driving a beta-gal reporter gene (to test that P-cadherin is activated by LEF-1 in vivo). Collectively, these findings will further our understanding of how LEF-1 controls follicle morphogenesis and how cell adhesion controls this morphogenetic process. In particular, this research will be of fundamental importance to our understanding of skin tumorigenesis, which in the case of basal cell carcinomas, is thought to arise from dedifferentiation of hair follicle cells and a subsequent reduction in cell adhesion.
| Dai, X; Schonbaum, C; Degenstein, L et al. (1998) The ovo gene required for cuticle formation and oogenesis in flies is involved in hair formation and spermatogenesis in mice. Genes Dev 12:3452-63 |
