Yy1 gene function in the bladder epithelium is essential for lower urinary tract morphogenesis

Urinary tract morphogenesis is a dynamic process depending on precise coordination between tissues derived from distinct embryonic lineages to establish a functional outflow tract. Disruption of urinary tract development can lead to congenital anomalies, which are among the most common defects diagnosed in neonates. A subset of these malformations arises from impaired distal ureter maturation, a process whereby the ureter separates from the nephric duct and integrates into the bladder wall. Abnormal ureter maturation can cause obstructive uropathies characterized by hydronephrosis and hydroureter. Despite their prevalence and clinical relevance, the molecular mechanisms regulating ureter maturation and obstruction remain poorly understood. Herein, we identify the ubiquitously expressed zinc-finger-containing transcription factor YY1 as an essential regulator of the lower urinary tract development in mice. Conditional inactivation of Yy1 function in the urogenital sinus (UGS), the embryonic bladder-urethra primordium, results in ureteral obstruction, hydronephrosis and hydroureter. Ureters fail to connect with bladder, a defect that correlates with loss of the UGS ridge, a transient structure required for ureter repositioning and maturation, as well as with reduced contractility at the UGS-nephric duct interface. Differentiation of the bladder urothelium is also disrupted, reflecting the YY1 cell-autonomous role in epithelial maturation. Integration of RNA-seq and YY1 chromatin occupancy data reveals that numerous differentially expressed genes are direct YY1 targets, several involved in mitochondrial function and homeostasis. Together, our findings establish YY1 as a key transcriptional regulator of bladder morphogenesis, coordinating ureter-bladder junction formation, promoting urothelial differentiation, and controlling mitochondrial gene networks critical for urinary tract development.