The central theme of this program project is the study of interactions of cell surface proteins in the development of the vertebrate embryo. Two of these proteins are involved in the differentiation of the nervous system and two others will be tested for their role in the morphogenesis of skin and the development of the bony skeleton. These surface proteins are being investigated at three levels of biological organization; the cell, the tissue and the organism. The NILE glycoprotein will be studied for its role in mediating interactions between nerve cells, and a new surface glycoprotein, GP90, will be investigated for its function in the communication of nerve cells with non-neuronal tissues such as muscle. A cell surface-associated heparan sulfate proteoglycan will be studied for its role in the morphogenesis of the embryonic skin, and the membrane glycoprotein alkaline phosphatase will be considered for a possible structural role in the morphogenesis of the skin and the bony skeleton. All projects will use the most up-to-date methods in recombinant DNA technology, immunology, protein chemistry and cell biology to investigate in detail the structure and function of these surface proteins that are highly relevant to vertebrate development. The structure of the proteins will be deduced from the nucleotide sequence of cDNAs that encode them. Their functions will be investigated by identifying the functional domains on the molecules themselves and of the ligands with which they interact. An animal model system for the human inherited disorder hypophosphatasia will be developed as part of one project by introducing mutated forms of the normal allele into the germ line of mice. This transgenic system will serve as a paradigm for later studies on the role of the other cell surface molecules in the development of vertebrate embryos. Two core facilities will be established for this program project. One will support the molecular biological studies and the second one will be established for the quantitative analysis of the behavior of cells as a function of the surface molecules that are being studied. With this facility we will be able to record, store and process images of cells behaving under defined conditions and evaluate changes in their shape and motility as a response to other cells or their extracellular matrix.
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