Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 996 - 1005 |
| Number of pages | 10 |
| Journal | Journal of Pediatric Urology |
| Volume | 9 |
| Issue number | 6 (Part B) |
| DOIs | |
| Publication status | Published - 2013 |
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New insights into the pathogenesis of bladder exstrophy-epispadias complex. / Mahfuz, Istiak; Darling, Tom; Wilkins, Simon; White, Stefan; Cheng, Wei.
In: Journal of Pediatric Urology, Vol. 9, No. 6 (Part B), 2013, p. 996 - 1005.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - New insights into the pathogenesis of bladder exstrophy-epispadias complex
AU - Mahfuz, Istiak
AU - Darling, Tom
AU - Wilkins, Simon
AU - White, Stefan
AU - Cheng, Wei
PY - 2013
Y1 - 2013
N2 - Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ?NP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.
AB - Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ?NP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.
UR - http://www.sciencedirect.com/science/article/pii/S1477513113001113
U2 - 10.1016/j.jpurol.2013.05.001
DO - 10.1016/j.jpurol.2013.05.001
M3 - Article
VL - 9
SP - 996
EP - 1005
JO - Journal of Pediatric Urology
JF - Journal of Pediatric Urology
SN - 1477-5131
IS - 6 (Part B)
ER -