Date of Award

1-1-2018

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Biological Sciences

Content Description

1 online resource (xiv, 99 pages) : illustrations (some color)

Dissertation/Thesis Chair

Melinda Larsen

Committee Members

Ben G Szaro, Prashanth Rangan, JoEllen Welsh

Keywords

atRA, development, RARα, RARγ, regeneration, salivary gland, Tretinoin, Salivary glands, Mice as laboratory animals, Vitamin A

Subject Categories

Cell Biology | Developmental Biology | Molecular Biology

Abstract

Controlled expansion and differentiation of progenitor cell populations is essential for organogenesis followed by continued maintenance of the population into and through adulthood. As the K5+ basal cell population is regulated by retinoic acid signaling, we interrogated the contribution of specific RAR isoforms to the regulation of these cells during submandibular salivary gland (SMG) organogenesis and regeneration. Retinoic acid has previously been shown to be involved in the development of the salivary gland, and recently, lack of retinoid signaling has been shown to impact the K5+ population of basal progenitor cells. Since retinoic acid is known to exert stimulatory effects on both epithelium and nerves, and during SMG development parasympathetic innervation has been shown to be necessary but not sufficient for maintenance of K5+ cells, in the first part of this study we investigated whether isoform-specific retinoic acid signaling changes the K5+ population. Using RAR isoform-specific antagonists and agonists in embryonic organ explants, we determined that RARα and RARγ have opposing effects on K5+ cell cycle progression. RARα negatively regulates, while RARγ positively maintains, K5+ cells in whole organ explants and in epithelial rudiments. Although retinoids are known to stimulate differentiation, in the developing gland K5 was not inversely correlated with ductal cytokeratins. Instead, RARα agonism and RARγ inhibition stimulated premature lumenization, as determined by prominin-1 (Prom-1) expression. With lineage tracing, we demonstrated that K5+ cells have the capacity to become Prom-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ cells in the developing submandibular salivary epithelium, independent of innervation, in a cell cycle-dependent manner. Additionally, in the developing gland, independent of keratinizing differentiation, the RARs control

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