p63 (TP73L) a key player in embryonic urogential development with significant dysregulation in human bladder exstrophy tissue
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 pict...
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Published in | International journal of molecular medicine Vol. 26; no. 6; pp. 861 - 867 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
D.A. Spandidos
01.12.2010
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Online Access | Get full text |
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Summary: | 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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ISSN: | 1107-3756 1791-244X |
DOI: | 10.3892/ijmm_00000535 |