Date of Award
Bachelor of Science
Salivary gland development in embryonic mouse occurs through the process of branching morphogenesis and differentiation to ultimately give rise to a fully functional, saliva-secreting adult gland. During branching morphogenesis, epithelial cells establish an apical and basal pole which determines the ultimate direction in which salivary fluid and proteins are secreted. Exactly how salivary tissue polarity is determined on a cellular and glandular level is not fully understood. Rac1, a member of the Rho GTPase family, is an intracellular signal transducer that has been shown in other cell types to regulate cell polarization. Rac1 is also important for the organization of apical adherens junction (e.g. E-cadherin) and tight junction (ZO-1, claudin-3) proteins. I hypothesized that Rac1 and its upstream activator, Tiam1, are required for salivary gland polarization. Previous data from our laboratory showed that chemical inhibitors of Rac1, NSC23766 and EHT1864, significantly inhibited growth and branching morphogenesis of embryonic E13 mouse submandibular salivary glands. Further, Rac1 inhibition also resulted in mislocalization of basement membrane matrix proteins to the apical side along with mislocalization of apical proteins, PAR3 and PAR6, to the basal side, hinting at a role for Rac1 during salivary gland branching morphogenesis and polarization. In this study, I found that inappropriate deposition of basement membrane proteins to the apical side was not due to aberrant endocytic vesicle trafficking upon Rac1 inhibition. I also confirmed that mislocalization and decreased expression of PAR proteins 3 and 6 and PKC zeta occurred with Rac1 inhibition, implicating Rac1 in mediating polarity since Rac1 inhibition deregulated the PAR, the master polarity regulator proteins. Further, I showed that the Rac1-specific guanine exchange factor (GEF), Tiam1, previously shown to be required for salivary gland branching morphogenesis, was not only strongly expressed by salivary gland cells, and localized basally, but it also decreased 5 with Rac1 inhibition suggesting a positive feedback loop with Rac1. The results of my study provide novel functions for Rac1 GTPase in the development and polarization of salivary glands and will eventually help us to understand the role of Rac1 in salivary gland disease conditions such as Sjögren‟s syndrome in which Rac1 expression is known to be deregulated.
Jin, Janice, "The Role of Rac1 Signaling in Tissue Polarity and Branching Morphogenesis During Salivary Gland Development" (2011). Biological Sciences. 54.