ΔNp63 plays an anti-apoptotic role in ventral bladder development

Abstract

The bladder, the largest smooth-muscle organ in the human body, is responsible for urine storage and micturition. P63, a homolog of the p53 tumor-suppressor gene, is essential for the development of all stratified epithelia, including the bladder urothelium. The N-terminal truncated isoform of p63, ΔNp63, is known to have anti-apoptotic characteristics. We have established that ΔNp63is not only the predominant isoform expressed throughout the bladder, but is also preferentially expressed in the ventral bladder urothelium during early development. We observed a host of ventral defects in p63-/- embryos, including the absence of the abdominal and ventral bladder walls. This number of ventral defects is identical to bladder exstrophy, a congenital anomaly exhibited in human neonates. In the absence of p63, the ventral urothelium was neither committed nor differentiated,whereas the dorsal urothelium was both committed and differentiated. Furthermore, in p63-/- bladders, apoptosis in the ventral urothelium was significantly increased. This was accompanied by the upregulation of mitochondrial apoptotic mediators Bax and Apaf1, and concurrent upregulation of p53. Overexpression ofΔ Np63γ and ΔNp63β in p63-/- bladder primary cell cultures resulted in a rescue,evidenced by significantly reduced expressions of Bax and Apaf1. We conclude that ΔNp63 plays a crucial anti-apoptotic role in normal bladder development.