Laminins mediate a variety of important processes involving cell-matrix interactions and show a remarkable diversity of tissue distribution and function. Work by our group during the current funding cycle implicates an essential role for laminin-10 in hair and appendage morphogenesis in the skin. We found that laminin-10 through binding with its receptor, (1 integrin, led to the expression of sonic hedgehog (SHH) to initiate the elongation of hair germs and subsequent steps in hair development. Remarkably, we found that exogenous laminin-10 rescued hair formation in lama5-/- mouse skin, however the domains of laminin-10 which perform this function and the mechanism of regulation of SHH expression by laminin-10 remains unclear. To localize the residues on laminin-10 which mediate hair development, we propose to test exogenous laminin G domains, as well as truncated and chimeric laminin trimers for their ability to rescue hair development in lama5-/- mouse skin. This proposal also seeks to elucidate the functional role of laminin-10 in hair follicle development. To this end, we will examine the effects of laminin-10 on the expression of early hair markers, focusing on potential upstream regulators of SHH expression. Other work from our group during the current cycle demonstrates that laminin-5 is required for squamous cell carcinoma (SCC) development. This proposal focuses on two domains of laminin-5, one of which is the region processed from the alpha3 chain, the G4-5 domain, which we have shown plays a critical role in carcinoma invasion. The other is the beta3 short arm, which may play an important role in stabilizing laminin-5 to the basement membrane, through interaction with type VII collagen and laminin-6. We seek to elucidate the function and localize the SCC promoting region of the G4-5 domain, evaluating the G4-5 domain as a potential molecular target for cancer therapy. We also seek to characterize the interactions between the laminin beta3 short arm with its putative ligands, type VII collagen and laminin-6, and examine its role in dermal-epidermal cohesion and carcinoma development.
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