| Research Abstract |
It has been postulated that ectopia of the initial ureter budding is the first ontogenic misstep that leads to many congenital anomalies of the kidney and urinary tract (CAKUT). The ectopia can result in hypoplastic kidney, ectopia of ureterovesical orifice, urinary outflow obstruction and/or reflux. Our studies on several mutant mouse models, e.g., Bmp4 +/-, Foxc1 -/-, Agtr2 -/Y, verified that ectopic ureter budding indeed occurs prior to the formation of CAKUT. Moreover we found that BMP4, acting on the Wolffian duct and ureter epithelium, determines the budding site of the ureter by locally antagonizing ubiquitous inductive signal(s) from the metanephric mesenchyme. However, analyses of Foxc1 -/-revealed that, whereas ectopic ureter can result in hypoplastic kidney and ureter morphological abnormality, it cannot cause formation of multicystic dysplastic kidney, a well-known renal abnormality seen in human CAKUT. Often, the genes involved in navigating the site of ureteral budding also regulate later ontogenic processes of the kidney and other urinary tract system. For example, BMP4 has multiple biological' functions during kidney and urinary tract formation as follows. In addition to determining budding site of the ureter, BMP4 (1) stimulates elongation of the budding ureter, 2) promotes growth of the metanephric mesenchyme by inhibiting apoptosis, and 3) has a role on the formation of glomerular tuft during glomerulogenesis. Thus, these additional functions of the genes underlie the wide spectrum of CAKUT, as the genes are expressed at multiple sites at multiple ontogenic stages, and regulate the morphogenesis of the many portions Qf the excretory system through their distinctive cellular functions.
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