title: New insights into the pathogenesis of bladder exstrophy-epispadias complex.
abstract: 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 ΔNP63 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.
authors.affiliation: Monash Institute of Medical Research, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia.
authors.forename: Istiak
authors.initials: I
authors.lastname: Mahfuz
authors.forename: Tom
authors.initials: T
authors.lastname: Darling
authors.forename: Simon
authors.initials: S
authors.lastname: Wilkins
authors.forename: Stefan
authors.initials: S
authors.lastname: White
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001746:Bladder Exstrophy / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D003896:Desmosomes / Q000502:physiology*; D004842:Epispadias / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
keywords: Bladder exstrophy; Desmosomes; Development; Gene expression; P63; PERP