Basement Membrane Biosynthesis

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DESCRIPTION (provided by applicant): Basement membranes are thin condensations of specialized extracellular matrix that underlie epithelia, surround muscle cells, and serve various physiological functions. Their pathological chemistry is important in several diseases, as well as in general medicine, development and aging. Their synthesis and modifications are not understood.We showed that some major constituents of basement membranes are very similar in man and Drosophila, established methodology for studying basement membrane formation in Drosophila, and in embryo cell cultures differentiating on known protein substrates, and proved the utility of this genetically accessible system. We found new basement membrane proteins first in Drosophila and later their homologues in man, mouse and nematode, specifically Papilin and Peroxidasin. Both proteins are essential for Drosophila embryogenesis. Stopping, or overexpressing, papilin synthesis disrupt normal cell arrangements of several organs, but not cell differentiation. Papilin occurs in most Drosophila and mouse basement membranes. Connective tissue synthesis and breakdown involve secreted ADAMTS metalloproteases, e.g. procollagen N-proteinase (ADAMTS2) processes a collagen precursor and aggrecanase (ADAMTS4) cuts several matrix components. ADAMTS enzymes and Papilins share a cassette of homologous protein domains, and interact. We shall investigate how such interactions may localize, modulate and control ADAMTS functions and organogenesis in Drosophila, in which we identified three ADAMTS enzymes, and in mice. Mouse Peroxidasin mRNA is widely distributed among organs. We shall ask whether mouse peroxidasin is a working peroxidase, and whether it occurs in basement membranes and phagocytic macrophages, as it does in Drosophila. It may serve in defense and/or in connecting tissues. Our investigations of Papilin and Peroxidasin have implications for connective tissue pathobiology.