Miyazaki Y, Oshima K, Fogo A, Hogan B L, Ichikawa I
Department of Pediatrics, Department of Pathology, Department of Cell Biology, and. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Clin Invest. 2000 Apr;105(7):863-73. doi: 10.1172/JCI8256.
In the normal mouse embryo, Bmp4 is expressed in mesenchymal cells surrounding the Wolffian duct (WD) and ureter stalk, whereas bone morphogenetic protein (BMP) type I receptor genes are transcribed either ubiquitously (Alk3) or exclusively in the WD and ureter epithelium (Alk6). Bmp4 heterozygous null mutant mice display, with high penetrance, abnormalities that mimic human congenital anomalies of the kidney and urinary tract (CAKUT), including hypo/dysplastic kidneys, hydroureter, ectopic ureterovesical (UV) junction, and double collecting system. Analysis of mutant embryos suggests that the kidney hypo/dysplasia results from reduced branching of the ureter, whereas the ectopic UV junction and double collecting system are due to ectopic ureteral budding from the WD and accessory budding from the main ureter, respectively. In the cultured metanephros deprived of sulfated glycosaminoglycans (S-GAGs), BMP4-loaded beads partially rescue growth and elongation of the ureter. By contrast, when S-GAGs synthesis is not inhibited, BMP4 beads inhibit ureter branching and expression of Wnt 11, a target of glial cell-derived neurotrophic factor signaling. Thus, Bmp4 has 2 functions in the early morphogenesis of the kidney and urinary tract. One is to inhibit ectopic budding from the WD or the ureter stalk by antagonizing inductive signals from the metanephric mesenchyme to the illegitimate sites on the WD. The other is to promote the elongation of the branching ureter within the metanephros, thereby promoting kidney morphogenesis.
在正常小鼠胚胎中，Bmp4在围绕中肾管（WD）和输尿管柄的间充质细胞中表达，而I型骨形态发生蛋白（BMP）受体基因要么普遍转录（Alk3），要么仅在WD和输尿管上皮中转录（Alk6）。Bmp4杂合缺失突变小鼠以高外显率表现出模仿人类先天性肾脏和尿路异常（CAKUT）的异常，包括肾发育不全/发育异常、输尿管积水、异位输尿管膀胱（UV）连接和双集合系统。对突变胚胎的分析表明，肾发育不全/发育异常是由于输尿管分支减少所致，而异位UV连接和双集合系统分别是由于WD处输尿管异位出芽和主输尿管副出芽所致。在缺乏硫酸化糖胺聚糖（S-GAGs）的培养后肾中，加载BMP4的珠子部分挽救了输尿管的生长和伸长。相比之下，当S-GAGs合成未被抑制时，BMP4珠子抑制输尿管分支和胶质细胞源性神经营养因子信号的靶标Wnt 11的表达。因此，Bmp4在肾脏和尿路的早期形态发生中具有两种功能。一种是通过拮抗后肾间充质向WD上非法位点的诱导信号来抑制WD或输尿管柄的异位出芽。另一种是促进后肾内分支输尿管的伸长，从而促进肾脏形态发生。
