Title: Roles in Retinoid Signaling in the Lower Urinary Tract
Description: Retinoic acid (RA)-signaling is involved in a broad spectrum of cellular processes, including formation of most embryonic tissues, epithelial differentiation, and is a critical regulator of stem cell differentiation in vitro. Studies from our lab have focused on the role of RA-signaling in the urinary tract, where we find that it plays multiple roles. By inducing expression of a floxed dominant-negative mutant Rar receptor, termed RaraDN, in the bladder, we find that RA-receptor signaling from the bladder epithelium plays distinct roles during urinary tract development; it is required for establishing mature ureter-bladder connections and for differentiation of the bladder epithelia. Congenital abnormalities of the kidney and urinary tract (CAKUT) characterize a range of lower urinary tract defects such as kidney and ureter agenesis, hydronephrosis, and vesicoureteral reflux. Development of the lower urinary tract, which consists of the kidneys, ureters, bladder, and urethra, is crucial for removal of toxic substances from the blood and depends on patent connections between the ureter and the bladder.

Impaired vitamin A signaling, either by maternal vitamin A deficiency in mice, or deleting RA-synthesizing enzymes and RA-receptors, leads to syndromic urinary tract abnormalities similar to those seen in humans. Our previous studies have suggested that proper ureter-bladder connections depend on signals derived from the bladder. By selectively inhibiting RA-signaling in the bladder epithelium, we show that RA-receptor signaling from the bladder is required for nephric duct (ND) insertion into the cloacal epithelium, CND maturation, and late-stage ureteral apoptosis in part through Ret. In addition, we find that RA acts independently of Ret where it regulates bladder growth and epithelial differentiation. The bladder epithelium, or urothelium, is a stratified epithelium that lines the major portion of the lower urinary tract and provides a crucial barrier between urine and blood. It contains basal, intermediate, and umbrella cells that synthesize and traffic uroplakin proteins to its apical surface.

Vitamin A has been shown to be necessary for preventing keratinization of the bladder epithelia, and in vitro, it can induce the differentiation of endodermal ES cells into populations of cells that express markers of the urothelium. Recent studies suggest that Shh-expressing population in the adult bladder contains progenitors that can repopulate the urothelium after damage. Here we report that RA-receptor-dependent signaling temporally regulates Shh-expressing urothelial progenitors and is required for formation of intermediate and umbrella cells during early development. Furthermore, we find that in the absence of RA-signaling, Shh-progenitors undergo a fate change, down-regulating uroplakins and up-regulating squamous markers, suggesting that RA is normally required for either positively regulating urothelial differentiation or negatively suppressing squamous differentiation.