This work was supported by grant 33CSCO-108792 from the Swiss National Science Foundation to RVK and SB (mental health core project of the Swiss Inflammatory Bowel Disease Cohort Study). The funding source was not involved in data collection, management, analysis, interpretation, or writing, ref 3 or in the decision to submit the manuscript for publication. RVK and SB provided the hypothesis, developed the case report forms, and coached RC. RC performed the literature search, analyzed the data, interpreted the results, and wrote the article. All authors revised the manuscript thoroughly and approved the present version. The authors have no conflicts of interest to declare. Conflicts of interest: None declared.
Mechanisms regulating the development of epithelial tissues associated with the mammalian urogenital system are poorly understood.

In particular, the sequential molecular cues necessary for the specification of the bladder urothelium have yet to be completely clarified. This transitional epithelium primarily serves as a highly selective permeability barrier protecting underlying tissues from toxic urinary components thereby preserving the integrity of the associated urinary tract and ultimately bladder and renal function [1]. Various congenital and acquired abnormalities including bladder and cloacal extrosphy [2], interstitial cystisis [3], neurogenic bladder secondary to myelomeningocele [4], and transitional cell carcinoma [5] are associated with aberrant urothelial differentiation and subsequent loss of normal barrier function.

In order to devise novel therapies to address these conditions, an increased understanding of the regulatory networks involved in urothelial development is required. The bladder urothelium is derived from the definitive endoderm [6], one of the three primary germ layers whose subsequent patterning and differentiation leads to the formation of a variety of major organs including the liver, pancreas, lungs, thyroid and intestines [7]. In the mouse, the definitive endoderm, together with mesoderm and ectoderm, is formed from the embryonic ectoderm of the epiblast through the process of gastrulation beginning at approximately day 6.5 of gestation [8]. The onset of bladder development begins with the formation of a transient embryonic cavity called the cloaca located at the caudal end of the hindgut, which is subsequently partitioned by the urorectal septum into a ventrally placed primitive urogenital sinus and dorsal anorectal canal by E8.

0 [9]�C[13]. Between E12�C15, the urothelium develops from the urogenital sinus into a multi-layered epithelium composed of axially subdivided basal, intermediate, and superficial cell layers [14]. Basal cells represent a germinative zone which differentiates towards the lumen into a pre-maturation population defined as Brefeldin_A intermediate cells, and finally into fully differentiated superficial cells.