Laboratory of Developmental Biology, Department of Medical Biochemistry and Molecular Biology, Center for Cell Matrix Research, Institute of Biomedicine Oulu, Biocenter Oulu, University of Oulu, Oulu, Finland.
PLoS One. 2011;6(11):e27676. doi: 10.1371/journal.pone.0027676. Epub 2011 Nov 17.
The epithelial ureteric bud is critical for mammalian kidney development as it generates the ureter and the collecting duct system that induces nephrogenesis in dicrete locations in the kidney mesenchyme during its emergence. We show that a secreted Bmp antagonist Cerberus homologue (Cer1) fine tunes the organization of the ureteric tree during organogenesis in the mouse embryo. Both enhanced ureteric expression of Cer1 and Cer1 knock out enlarge kidney size, and these changes are associated with an altered three-dimensional structure of the ureteric tree as revealed by optical projection tomography. Enhanced Cer1 expression changes the ureteric bud branching programme so that more trifid and lateral branches rather than bifid ones develop, as seen in time-lapse organ culture. These changes may be the reasons for the modified spatial arrangement of the ureteric tree in the kidneys of Cer1+ embryos. Cer1 gain of function is associated with moderately elevated expression of Gdnf and Wnt11, which is also induced in the case of Cer1 deficiency, where Bmp4 expression is reduced, indicating the dependence of Bmp expression on Cer1. Cer1 binds at least Bmp2/4 and antagonizes Bmp signalling in cell culture. In line with this, supplementation of Bmp4 restored the ureteric bud tip number, which was reduced by Cer1+ to bring it closer to the normal, consistent with models suggesting that Bmp signalling inhibits ureteric bud development. Genetic reduction of Wnt11 inhibited the Cer1-stimulated kidney development, but Cer1 did not influence Wnt11 signalling in cell culture, although it did inhibit the Wnt3a-induced canonical Top Flash reporter to some extent. We conclude that Cer1 fine tunes the spatial organization of the ureteric tree by coordinating the activities of the growth-promoting ureteric bud signals Gndf and Wnt11 via Bmp-mediated antagonism and to some degree via the canonical Wnt signalling involved in branching.
输尿管芽对于哺乳动物肾脏发育至关重要，因为它在肾脏间质中诱导肾发生，在肾脏间质中诱导肾发生，在肾脏间质中诱导肾发生，在肾脏间质中诱导肾发生。我们表明，一种分泌的 Bmp 拮抗剂 Cerberus 同源物（Cer1）在小鼠胚胎器官发生过程中精细地调节输尿管树的组织。增强的输尿管 Cer1 表达和 Cer1 敲除都会增大肾脏的大小，这些变化与光学投影断层扫描显示的输尿管树的三维结构改变有关。增强的 Cer1 表达改变了输尿管芽的分支程序，使得更多的三叉和侧支而不是二叉分支发育，如延时器官培养中所见。这些变化可能是 Cer1+胚胎肾脏中输尿管树的空间排列改变的原因。Cer1 功能获得与 Gdnf 和 Wnt11 的适度上调有关，在 Cer1 缺失的情况下，也诱导了 Bmp4 表达的减少，这表明 Bmp 表达依赖于 Cer1。Cer1 在细胞培养中结合至少 Bmp2/4 并拮抗 Bmp 信号。与此一致，补充 Bmp4 恢复了输尿管芽尖端的数量，Cer1+降低了输尿管芽尖端的数量，使其更接近正常水平，与模型一致，表明 Bmp 信号抑制输尿管芽的发育。Wnt11 的遗传减少抑制了 Cer1 刺激的肾脏发育，但 Cer1 在细胞培养中没有影响 Wnt11 信号，尽管它在某种程度上抑制了 Wnt3a 诱导的经典 Top Flash 报告基因。我们得出结论，Cer1 通过协调生长促进的输尿管芽信号 Gndf 和 Wnt11 的活性，通过 Bmp 介导的拮抗作用，在一定程度上通过涉及分支的经典 Wnt 信号来精细调节输尿管树的空间组织。
