The process of secretion happens in all cells, from the very low levels characteristic of most cells, to the extremely high levels found in organs specialized for secretion. The goal of this proposal is to determine the transcriptional mechanisms that drive secretory capacity and to identify novel genes required for the development and function of the specialized secretory organs, including the pancreas, submandibular and mammary glands. We know from previous work that the bZip transcription factor, CrebA, is the major regulator of secretion, however, our data suggests that upregulation of secretory capacity requires additional transcription factors that act downstream of CrebA. Microarray analysis identified 16 transcription factors that depend on CrebA for normal expression. During the mentored phase of the award, research will focus on the characterization of one of these, Tudor-SN.
The first aim of this proposal will characterize the role of Tudor-SN in secretory organ development, and determine the mechanism of Tudor-SN function on secretory capacity. The microarray screen also identified over 100 new/novel genes that have not been previously implicated in secretory function and that have human homologues, of which nineteen have documented expression in the salivary gland. The independent phase of this project will use both the Drosophila salivary gland system and human secretory cells to identify and characterize genes with novel roles in the secretory pathway. We know that CrebA is highly conserved in humans, and that its homologues, Creb3L1 and Creb3L2 also have important roles in secretory activity. Thus our studies using the Drosophila salivary gland will allow us to identify genes with important roles in the development and function of secretory organs in humans. The ultimate goal of this career development award is to establish the Drosophila salivary gland as a model system for studying how secretory organs develop secretory capacity, while at the same time building a competitive research program that will provide a good foundation for when I set up my own laboratory.
Many human diseases result from secretory dysfunction, including diabetes, pancreatitis, Sj""""""""gren's syndrome and multiple myeloma. Understanding how secretory organs develop the capacity to secrete the large amounts of protein required for normal function is essential to developing new therapeutic strategies to treat these diseases.
|Fox, Rebecca M; Andrew, Deborah J (2015) Changes in organelle position and epithelial architecture associated with loss of CrebA. Biol Open 4:317-30|
|Fox, Rebecca M; Andrew, Deborah J (2015) Transcriptional regulation of secretory capacity by bZip transcription factors. Front Biol (Beijing) 10:28-51|
|Fox, Rebecca M; Vaishnavi, Aria; Maruyama, Rika et al. (2013) Organ-specific gene expression: the bHLH protein Sage provides tissue specificity to Drosophila FoxA. Development 140:2160-71|
|Barbosa, Sónia; Fasanella, Giovanna; Carreira, Suzanne et al. (2013) An orchestrated program regulating secretory pathway genes and cargos by the transmembrane transcription factor CREB-H. Traffic 14:382-98|
|Fox, Rebecca M; Hanlon, Caitlin D; Andrew, Deborah J (2010) The CrebA/Creb3-like transcription factors are major and direct regulators of secretory capacity. J Cell Biol 191:479-92|