DeltaNp63 plays an anti-apoptotic role in ventral bladder development.
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, DeltaNp63, is known to have anti-apoptotic characteristics. We have established that DeltaNp63 is 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 of DeltaNp63gamma and DeltaNp63beta in p63-/- bladder primary cell cultures resulted in a rescue, evidenced by significantly reduced expressions of Bax and Apaf1. We conclude that DeltaNp63 plays a crucial anti-apoptotic role in normal bladder development.
Cheng
Wei
W
Department of Surgery, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
Jacobs
W Bradley
WB
Zhang
Jennifer J R
JJ
Moro
Anne
A
Park
Jin-Hyung
JH
Kushida
Michelle
M
Qiu
Wei
W
Mills
Alea A
AA
Kim
Peter C W
PC
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D001483:Base Sequence; D001746:Bladder Exstrophy / Q000196:embryology / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000196:embryology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001743:Urinary Bladder / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D019459:Urothelium / Q000166:cytology / Q000196:embryology / Q000378:metabolism
D017931:DNA Primers; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse