Secrets of secretion—How studies of the Drosophila salivary gland have informed our understanding of the cellular networks underlying secretory organ form and function

Secretory organs are critical for organismal survival. Yet, the transcriptional regulatory mechanisms governing their development and maintenance remain unclear for most model secretory organs. The Drosophila embryonic salivary gland (SG) remedies this deficiency as one of the few organs wherein direct connections from the expression of the early patterning genes to cell specification to organ architecture and functional specialization can be made. Few other models of secretion can be accorded this distinction. Studies from the past three decades have made enormous strides in parsing out the roles of distinct transcription factors (TFs) that direct major steps in furnishing this secretory organ. In the first step of specifying the salivary gland, the activity of the Hox factors Sex combs reduced, Extradenticle, and Homothorax activate expression of fork head (fkh), sage, and CrebA, which code for the major suite of TFs that carry forward the task of organ building and maintenance. Then, in the second key step of building the SG, the program for cell fate maintenance and morphogenesis is deployed. Fkh maintains the secretory cell fate by regulating its own expression and that of sage and CrebA. Fkh and Sage maintain secretory cell viability by actively blocking apoptotic cell death. Fkh, along with two other TFs, Hkb and Rib, also coordinates organ morphogenesis, transforming two plates of precursor cells on the embryo surface into elongated internalized epithelial tubes. Acquisition of functional specialization, the third key step, is mediated by CrebA and Fkh working in concert with Sage and yet another TF, Sens. CrebA directly upregulates expression of all of the components of the secretory machinery as well as other genes (e.g., Xbp1) necessary for managing the physiological stress that inexorably accompanies high secretory load. Secretory cargo specificity is controlled by Sage and Sens in collaboration with Fkh. Investigations have also uncovered roles for various signaling pathways, e.g., Dpp signaling, EGF signaling, GPCR signaling, and cytoskeletal signaling, and their interactions within the gene regulatory networks that specify, build, and specialize the SG. Collectively, studies of the SG have expanded our knowledge of secretory dynamics, cell polarity, and cytoskeletal mechanics in the context of organ development and function. Notably, the embryonic SG has made the singular contribution as a model system that revealed the core function of CrebA in scaling up secretory capacity, thus, serving as the pioneer system in which the conserved roles of the mammalian Creb3/3 L-family orthologues were first discovered.