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p63 (TP73L) a key player in embryonic urogential development with significant dysregulation in human bladder exstrophy tissue

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Human bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of urogenital anomalies in which part or all of the distal urinary tract fails to close. Several lines of evidence implicate genetic factors in the formation of BEEC. Among them a murine p63+/+ knockout model showed the full picture of classic exstrophy of the bladder and other urogenital defects within the BEEC spectrum. This led us to study in depth the role of p63 in urogenital development in mice and investigate the implication of p63 in human BEEC. Whole mount in situ analysis in mice was carried out to investigate the ventro-caudal expression of the p63 transcript at gestational days (GD) 9.5-12.5, the equivalent of human gestational weeks 4-6 (postulated time of BEEC organogenesis in humans). In addition, p63 expression analysis was performed in human blood and bladder derived samples of 15 BEEC newborns accompanied by sequencing analysis of their genomic DNA. We also conducted sequencing analysis of genomic DNA in additional 22 BEEC patients. In mouse embryos, p63 expression was detected at days 9.5-12.5 in the cloacal membrane and urethral epithelium, supporting its role in the morphogenesis of the external genitalia and the bladder. Tissue-specific expression of a novel and already-known mRNA isoforms were established and a reproducible dysregulation of variable p63 isoforms was observed in 11 of 15 patients indicating altered gene expression. However, no obvious p63 gene mutations were identified in any of the patients. Our findings strongly suggest that p63 is not only involved in embryonic formation of the urogenital and ventrocaudal anatomy but is also highly dysregulated in human BEEC bladder tissue. Since p63 has been shown to self-regulate its expression through a balance of its isoforms, the dysregulation observed may contribute to the formation of BEEC.
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Document Type: Research Article

Affiliations: Section of Genetics, Department of Pediatrics, University of California Davis, Sacramento, CA 95817, USA

Publication date: December 1, 2010

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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