Abstract
PURPOSE Congenital bladder abnormalities, such as posterior urethral valves and persistent cloaca are often devastating diseases. In addition, bladder tumours can be viewed as defects in differentiation. To understand the pathobiology of these disorders we must first unravel the cell biology of normal bladder development and we therefore undertook a comprehensive gene screen using the mouse as a model. MATERIAL AND METHODS We extracted high-quality mRNA (n = 3 for each time point) from normal mouse bladders at embryonic day 13 and day 18 (anatomically equivalent to human 7 and 13 week gestation). The mouse bladder originates from the cloaca and by embryonic day 13 it can be isolated as a discrete unit; by day 18 the organ has differentiated into urothelium and smooth muscle. cDNA was hybridised to the Affymetrix Mouse MOE430v2 U133 array and differential gene expression analysed. RESULTS As expected and therefore validating the current system, genes associated with detrusor smooth muscle and innervation were upregulated in the embryonic day 18 bladder, and epithelial differentiation genes (keratins, uroplakins and claudins) were also prominent. Aquaporins 1/3 and the purinergic receptor P2rx1 were detected as were components of the angiotensin signalling system. In contrast, the genetic landscape in the initiating bladder was quite different. It was dominated by the expression of transcription factors (Hox, Gata and Tbx families) and retinoic acid signalling genes. Also prominent were numerous members of the Eph/Ephrin bidirectional signalling families; when mutated these give rise to cloacal and anorectal malformations in mice. In addition, we detected upregulation of Frem1 and Grip1, which are Fraser syndrome-related genes, and we note that this disorder features bladder malformations including agenesis. CONCLUSIONS This data provides novel insights into molecules that orchestrate normal bladder development as well as diseases associated with abnormal differentiation.
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