Development of congenital anomalies of the kidney and urinary tract (CAKUT)

据推测，最初的输尿管发芽异位是导致许多先天性肾和尿路畸形(CAKUT)的第一个个体错误。异位可导致肾发育不良、输尿管膀胱口异位、尿流出道梗阻和/或反流。我们对Bmp4/-、Foxc1-/-、Agtr2-/Y等突变小鼠模型的研究证实，异位输尿管萌芽确实发生在CAKUT形成之前。此外，我们还发现，作用于Wolffian管和输尿管上皮的BMP4通过局部拮抗来自后肾间充质的无处不在的诱导信号(S)来决定输尿管的出芽位置。然而，对Foxc1-/-的分析表明，尽管异位输尿管可以导致肾脏发育不良和输尿管形态异常，但它不会导致多囊发育不良肾的形成，这是一种在人类CAKUT中常见的肾脏异常。通常，参与导航输尿管萌发部位的基因也调节肾脏和其他尿路系统后来的个体发生过程。例如，BMP4在肾脏和尿路形成过程中具有多种生物学功能，如下所示。除了确定输尿管的萌发部位外，BMP4(1)刺激萌芽的输尿管延长，2)通过抑制细胞凋亡促进后肾间充质的生长，以及3)在肾小球形成过程中对肾小球簇状的形成起作用。因此，这些基因的这些附加功能构成了CAKUT广谱的基础，因为这些基因在多个个体发生阶段的多个位置表达，并通过其独特的细胞功能调节排泄系统许多部分的形态发生。

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.