MECHANISMS OF SALIVARY GLAND DEVELOPMENT

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The rodent submandibular gland (SMG) poses an excellent system to study the development of secretory epithelium because several secretory cell types arise along a common duct and the gland does not reach maturity until 3 to 4 months of age. Furthermore, the potential for changing the proportions of these ductal secretory cells is retained throughout adulthood. By utilizing specific cell type marker, differentiation of various cell types can be racked back through development. Acinar cells (AC) do not appear until 3 days after birth, yet immunoquantitation studies of mucin, an AC marker, indicate that mucin is present in prenatal animals, prior to the appearance of AC. The pattern of accumulation for mucin is a biphasic nature, indication that AC pass through a protodifferentiated stage prior to cytodifferentiation. Sensitive protein synthesis assays will be performed to verify that mucin synthesis occurs during this stage. Immunoquantitation and protein synthesis studies on epidermal growth factor (EGF) will determine if granular convoluted tubule cells (GCT) likewise pass thought a protodifferentiated stage. Cloning of prenatal and adult SMG will be performed determine whether GCT and AC share a common stem cell during development and for cell replacement in adults. The link between differentiation and cell replacement will be pursued further by isolating pure GCT and pure Ac populations by cell sorting and then testing to see if each differentiated cell type retains the protodifferentiated capability for the other. Recent studies have shown that mucin is present in the granular intercalated duct cell (GID) from adult female glands. Perhaps these cells are an intermediate in the AC replacement process. By utilizing results from 3-D reconstructions and DNA labelling of secretory units, an indication should be provided as to whether or not striated secretory tubule cells (SST) and GID are intermediates of GCT and AC, respectively, in the replacement process. These observations may also provide evidence for a pleuripotent stem cell in adults or conversely, for individual progenitor cell lines for each secretory cell type. Ultimately, we are tying to determine at what stage secretory cell divergence occurs in the sequence of development of submandibular gland and to identify the level of gene control that is responsible.