ΔNp63 plays an anti-apoptotic role in ventral bladder development
ΔNp63 plays an anti-apoptotic role in ventral bladder development
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DOI：
10.1242/dev.02621
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发表时间：
2006-12-01
期刊：
影响因子：
4.6
通讯作者：
Kim, Peter C. W.
中科院分区：
文献类型：
--
作者：
Cheng, Wei;Jacobs, W. Bradley;Kim, Peter C. W.
膀胱是人体内最大的平滑肌器官，负责尿液储存和排尿。p63是p53肿瘤抑制基因的同源基因，对所有复层上皮（包括膀胱尿路上皮）的发育至关重要。p63的N末端截短异构体ΔNp63具有抗凋亡特性。我们已经确定，ΔNp63不仅是在整个膀胱中表达的主要异构体，而且在早期发育过程中在膀胱腹侧尿路上皮中优先表达。我们在p63（-/-）胚胎中观察到许多腹侧缺陷，包括腹部和膀胱腹侧壁缺失。这种腹侧缺陷的数量与膀胱外翻相同，膀胱外翻是人类新生儿出现的一种先天性异常。在没有p63的情况下，膀胱腹侧尿路上皮既未定型也未分化，而背侧尿路上皮既已定型又已分化。此外，在p63（-/-）膀胱中，膀胱腹侧尿路上皮的凋亡显著增加。这伴随着线粒体凋亡介质Bax和Apaf1的上调，以及p53的同时上调。在p63（-/-）膀胱原代细胞培养物中过表达ΔNp63γ和ΔNp63β可实现挽救，表现为Bax和Apaf1的表达显著降低。我们得出结论，ΔNp63在正常膀胱发育中起着关键的抗凋亡作用。
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 Np63 beta 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.