Many people suffer from loss of salivary gland function. Thus, knowledge of salivary gland biology is an important research goal. Elucidating the developmental mechanisms that regulate organogenesis of a salivary gland within an embryo is a necessary first step toward developing therapies to replace or regenerate damaged glands. Key issues that can be addressed by examining embryonic salivary gland development include identifying the biological signals that stimulate growth and branching of the saliva-producing gland epithelium, or that stimulate growth of essential gland nerves. Utilizing our expertise in developmental biology, and mouse genetic tools for the study of Vitamin A metabolism, we have recently identified that enzymatic metabolism of Vitamin A to produce the powerful hormone-like molecule Retinoic Acid is an essential biological mechanism regulating embryonic development of submandibular salivary glands. We have shown that Retinoic Acid regulates growth and branching of salivary gland epithelium in vivo and in vitro. For the current study, we propose to investigate what cellular processes of epithelium branching growth are regulated by Retinoic Acid. We will examine embryonic salivary gland development in mice with a mutation in Rdh10, which are deficient in production of Retinoid Acid because they lack the major enzyme responsible for metabolism of Vitamin A. We will determine whether the defects in growth and branching of salivary gland epithelium result from abnormal cell proliferation, basement membrane remodeling, or formation of stable clefts between branches. We will complement our analysis of mouse embryonic glands by examining salivary glands grown in culture. These experiments will allow us to determine which cellular mechanisms of epithelium growth and branching are regulated by Retinoic Acid signaling. For the current investigation, we propose also to examine the role of Retinoic Acid in regulating development of essential salivary gland nerves. We will determine if Retinoic Acid signaling regulates neuron number or neurite outgrowth, and will determine if Retinoic Acid impacts nerve development via direct action in non-epithelial gland tissues, or if Retinoic Acid impacts nerve formation indirectly, via influence on the epithelium. Knowledge gained from this study will serve as the groundwork for understanding how retinoid molecules impact salivary gland tissue morphogenesis.
Knowledge of embryonic organ formation is a necessary first step toward developing therapies to restore or replace damaged salivary glands. We have recently identified that the powerful hormone-like molecule Retinoic Acid is an essential biological regulator of embryonic salivary gland development. For the current study, we propose to investigate how Retinoic Acid controls formation of the saliva-producing epithelium and essential nerve tissue in developing submandibular salivary glands in mice.
