Defining the mechanisms of secretion in the Drosophila salivary gland

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DESCRIPTION (provided by applicant): Many specialized organs require high-level secretory activity to perform their normal functions. For example, in the immune system, B-cells differentiate into plasma cells by up-regulating the secretory machinery, thereby acquiring the ability to secrete large amounts of antibodies that fight infection and disease. Also, the pancreas secretes digestive enzymes that aid in food metabolism, as well as hormones that regulate blood glucose levels (i.e. glucagons and insulin). Correspondingly, loss of secretory control has been attributed to the pathogenesis of many human diseases, including pancreatitis and diabetes, as well as the blood cancer, multiple myeloma. One key to understanding secretory organ development and function is to define the mechanisms whereby normal cells gain the ability to secrete large amounts of protein. To do this, I will use a model system, the Drosophila salivary gland, which is the largest secretory organ in this organism and consists of cells that are specialized for high-level secretion. Two salivary gland expressed transcription factors (proteins that regulate expression of other genes) CrebA and Xbp1, have a role in regulating secretory activity. CrebA is required for the high level expression of 34 known secretory pathway component genes in the salivary gland. Consistent with this finding, CrebA mutants exhibit defects in secretory function. Xbp1 is a highly conserved transcription factor involved in ER stress response and whose mammalian counterpart is normally required for B-cells to become antibody secreting plasma cells. In Drosophila, Xbp1 is highly expressed in the embryonic salivary gland. Thus, I propose that CrebA and Xbp1 may function cooperatively to initiate and maintain the high-level secretory function of this organ. My studies will determine if CrebA and Xbp1 work in the same or parallel pathways to mediate secretory activity, if CrebA and xbpl mutants have defects in the secretory machinery, and if CrebA and/or Xbp1 directly regulate expression of the genes required to make this machinery. Finally, I will identify all of the genes that depend on CrebA and Xbp1 for their expression in the salivary gland, potentially revealing additional factors necessary for secretory function. Since both CrebA and Xbp1 homologues exist in humans, the mechanisms required to regulate secretory activity in the Drosophila salivary gland are likely to be conserved. Thus, these studies will provide a foundation for the development of therapeutics to treat diseases characterized by secretory dysfunction.