Retinoic Acid Signaling in Salivary Gland Organogenesis

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Abstract Understanding how an embryo builds an organ during development is essential to inform studies into regenerating tissue in vitro. There is currently a clinical need to regenerate salivary glands for patients who have suffered permanent gland damage due to radiation therapy or autoimmune disease. The resulting chronic xerostomia (dry mouth) leads to a sharp decline in oral health and quality of life. The ability to construct functioning gland for these patients would restore saliva to the oral cavity, which includes many beneficial components involved in functions such as antimicrobial protection, pH balance, digestion, lubrication, and remineralization. Many current studies in salivary gland development have elucidated the signaling molecules necessary for several important processes such as branching morphogenesis, lumen formation, cell differentiation, and progenitor cell maintenance. Studies in the field have also shown that early salivary gland development is dependent on both the epithelium and enervation from the closely associated parasympathetic ganglion (PSG). However, very little is known about the earliest stages of gland development, and no studies have been done on the signaling molecules needed to control salivary gland initiation or PSG formation. The gap in knowledge is likely due to the lack of experimental models for the earliest phases of gland organogenesis. In preparation for this proposal, I have established a novel ex vivo culture system utilizing mouse embryo tissues to assay salivary gland initiation. This is an important development for the field in that it allows researchers to answer questions they could not before. With this system, I have generated preliminary data showing that RA signaling is required for submandibular gland (SMG) initiation and development of the parasympathetic ganglion (PSG). Blocking RA signaling represses gland bud initiation, and, conversely, supplementation with retinol (vitamin A) enhances initiation. Moreover, I have identified that the size of the initial PSG is reduced, with a fewer number of cells, when RA signaling is blocked. In this proposal, I will investigate the role of vitamin A metabolism by the retinol oxidizing enzyme RDH10 in initiation of the SMG epithelium, and the role of RA signaling on PSG formation.