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First published online 1 November 2006
doi: 10.1242/dev.02621

Development 133, 4783-4792 (2006)
Published by The Company of Biologists 2006
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{Delta}Np63 plays an anti-apoptotic role in ventral bladder development

Wei Cheng1,2, W. Bradley Jacobs3, Jennifer J. R. Zhang1,2, Anne Moro1,2, Jin-Hyung Park1,2, Michelle Kushida1,2, Wei Qiu2, Alea A. Mills4 and Peter C. W. Kim1,2,*

1 Department of Surgery, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
2 Program for Infection, Immunity, Injury and Repair, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
3 Program of Developmental Biology, Hospital for Sick Children, Toronto, M5G 1X8, Canada.
4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.

* Author for correspondence (e-mail: peter.kim{at}sickkids.ca)

Accepted 8 September 2006

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, {Delta}Np63, is known to have anti-apoptotic characteristics. We have established that {Delta}Np63 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 {Delta}Np63{gamma} and {Delta}Np63ß in p63-/- bladder primary cell cultures resulted in a rescue, evidenced by significantly reduced expressions of Bax and Apaf1. We conclude that {Delta}Np63 plays a crucial anti-apoptotic role in normal bladder development.

Key words: p63, Bladder exstrophy, Apoptosis, Mouse




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[Abstract] [Full Text] [PDF]


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