Basement membranes are thin sheets of specialized extracellular matrix that surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They are thought to play roles in filtration, in tissue integrity and compartmentalization, and in cell adhesion, proliferation, migration, and differentiation. Defects in basement membranes are responsible for a diverse array of human diseases, and the phenotypes of knockout mice show that basement membranes play critical roles during development and in mature tissues. The broad, long term goals of the research proposed here are to understand 1) the functions of basement membranes in mammalian development and physiology, and 2) how heterogeneity in basement membrane composition translates into functional specificity in vivo. We are particularly interested in one major component of all basement membranes, laminin. We previously showed that laminin alpha5 which is widely expressed, plays a crucial role in multiple developmental processes, including placentation and kidney development. In addition, replacement of alpha5 with a chimeric laminin in vivo demonstrated that the globular (G) domain of alpha5 is required for mesangial cell-mediated organization of the kidney glomerular capillaries. Here we will focus on the roles of the laminin alpha1 and alpha5 G domains in early embryogenesis and in formation of the placenta. We will also determine the cellular origin of the placental morphogenesis defect using Cre/lox technology. In addition, we will test the hypothesis that defects observed in the laminin alpha5 knockout stem in part from alterations in BMP signaling, which could result from abnormal interactions of BMPs or their antagonists with the extracellular matrix. The results of these studies will lead to new information regarding the assembly and function of laminins in the in vivo setting.
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