Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development
Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development
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DOI：
10.1046/j.1523-1755.2003.00834.x
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发表时间：
2003-03-01
影响因子：
19.6
通讯作者：
Ichikawa, I
中科院分区：
文献类型：
--
作者：
Miyazaki, Y;Oshima, K;Ichikawa, I
背景我们已经提出，骨形态发生蛋白4（BMP 4），作用于沃尔夫管和输尿管上皮，决定了输尿管的出芽位点，通过局部拮抗无处不在的诱导信号（S）从后肾间充质。在本研究中，我们研究了BMP 4对后肾和输尿管周围间充质细胞发育的影响，这些细胞表达BMP I型受体基因Bmpr 1a（Alk 3）。从不同阶段的Bmp 4杂合无效突变（Bmp 4 +/-）胚胎中获得的泌尿生殖系统组织，以及在重组BMP 4存在下培养的后肾和输尿管组织外植体进行形态学、免疫组化和原位杂交分析。为了检测BMP 4对输尿管周围间充质细胞的趋化活性，进行了改良的Boyden室测定。新生Bmp 4 +/-小鼠的许多肾脏含有多囊性发育不良区域。在E14.5时，突变胚胎的后肾间充质中异常高的凋亡活性导致了这种形态。在整个后肾外植体，BMP 4均匀地促进扩张的Pax 2阴性和弱Foxd 1（以前Bf 2）阳性外周间质隔室的后肾间质成纤维细胞生长因子2（FGF 2）的存在下。此外，在分离的后肾间充质中，负载BMP 4的珠粒局部防止细胞凋亡。因此，BMP 4防止细胞死亡并促进后肾间充质的生长。BMP 4对输尿管周围间质的作用与对后肾间质的作用不同。在子宫内，输尿管周围的间充质细胞聚集在输尿管上皮周围，然后在Bmp 4强烈表达的部位分化为平滑肌细胞。在E15.5时对Bmp 4 +/-输尿管的分析表明，α-平滑肌肌动蛋白（α-SMA）阳性细胞数量较少。在体外，负载BMP 4的珠粒促进输尿管周围间充质细胞的积累，以形成珠粒周围的几个细胞层。此外，在Boyden室测定中，BMP 4增加输尿管周围间充质细胞通过滤器的迁移。因此，BMP 4可以作为输尿管周围间充质细胞的化学引诱物，并在局部诱导表达BMP 4的输尿管平滑肌层。根据局部情况，BMP 4对排泄系统不同部分的形态发生具有几种生物学作用，即输尿管膀胱连接部、输尿管和肾脏的发育。
Background. We have suggested that bone morphogenetic protein 4 (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. In the present study, we examine the effect of BMP4 on the development of metanephric and periureteral mesenchymal cells, which express the BMP type I receptor gene, Bmpr1a (Alk3 ).Methods. Urogenital tissues obtained from Bmp4 heterozygous null mutant (Bmp4 +/-) embryos at different stages, and metanephric and ureteral tissue explants cultured in the presence of recombinant BMP4 were subjected to morphologic, immunohistochemical and in situ hybridization analyses. To examine the chemotactic activity of BMP4 for periureteral mesenchymal cells, a modified Boyden chamber assay was performed.Results. Many of the kidneys of newborn Bmp4 +/- mice contained multicystic dysplastic regions. This morphology was preceded by abnormally high apoptotic activity in the metanephric mesenchyme of mutant embryos at E14.5. In whole metanephric explants, BMP4 uniformly promoted the expansion of the Pax2 -negative and weakly Foxd1 (previously Bf2)-positive peripheral stromal compartment of metanephric mesenchyme in the presence of fibroblast growth factor 2 (FGF2). In addition, in isolated metanephric mesenchyme, BMP4-loaded beads prevented apoptosis locally. Thus, BMP4 prevents cell death and promotes the growth of the metanephric mesenchyme. The effect of BMP4 on periureteral mesenchyme is different from its effect on metanephric mesenchyme. In utero, periureteral mesenchymal cells condense around the ureter epithelium, followed by differentiation into smooth muscle cells at a site where Bmp4 is intensely expressed. Analysis of Bmp4 +/- ureters at E15.5 reveals that the alpha-smooth muscle actin (alpha-SMA)-positive cells are low in number. In vitro, BMP4-loaded beads promote the accumulation of periureteral mesenchymal cells to form several cell layers surrounding the beads. In addition, in a Boyden chamber assay, BMP4 increases the migration of periureteral mesenchymal cells through the filter. Thus, BMP4 can serve as a chemoattractant for periureteral mesenchymal cells and induce locally the smooth muscle layer of the ureter at Bmp4-expressing sites.Conclusion. Depending on local context, BMP4 has several biological actions on the morphogenesis of different portions of the excretory system, namely, the development of the ureterovesical junction, the ureter, and the kidney.