Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter
Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter
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DOI：
10.1172/jci8256
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发表时间：
2000-04-01
影响因子：
15.9
通讯作者：
Ichikawa, I
中科院分区：
文献类型：
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作者：
Miyazaki, Y;Oshima, K;Ichikawa, I
在正常小鼠胚胎中，Bmp4在Wolffian管(WD)和输尿管柄周围的间充质细胞中表达，而骨形态发生蛋白(BMP)I型受体基因在WD和输尿管上皮中普遍转录(Alk3)或仅在WD和输尿管上皮中转录(Alk6)。BMP4杂合缺失突变小鼠表现出高外显率，表现为模仿人类先天性肾脏和尿路异常(CAKUT)的异常，包括肾脏发育不良/发育不良、输尿管积水、异位输尿管膀胱(UV)连接和双收集系统。对突变胚胎的分析表明，肾脏发育不良是由于输尿管分支减少所致，而异位UV连接和双收集系统分别是由于来自WD的异位输尿管发芽和来自主输尿管的副发芽。在培养的不含硫酸氨基葡聚糖的后肾细胞(S-GAGS)中，骨形态发生蛋白4微球部分挽救了输尿管的生长和延长。相反，当S-GAGS的合成没有被抑制时，BMP4微球抑制输尿管分支和WNT11的表达，WNT11是胶质细胞衍生神经营养因子信号转导的靶标。因此，Bmp4在肾脏和尿路的早期形态发生中具有2个功能。一种是通过拮抗后肾间充质对WD上非法部位的诱导信号来抑制WD或输尿管柄的异位萌发。另一种是促进后肾内分支输尿管的延长，从而促进肾脏的形态发生。
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 Wnt11, a target of glial cell-derived neuro trophic 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.