Developmental Genetics, Department of Biomedicine, University of Basel Medical Faculty, Basel, Switzerland.
PLoS One. 2011 Apr 28;6(4):e19370. doi: 10.1371/journal.pone.0019370.
Genetic analysis in the mouse revealed that GREMLIN1 (GREM1)-mediated antagonism of BMP4 is essential for ureteric epithelial branching as the disruption of ureteric bud outgrowth and renal agenesis in Grem1-deficient embryos is restored by additional inactivation of one Bmp4 allele. Another BMP ligand, BMP7, was shown to control the proliferative expansion of nephrogenic progenitors and its requirement for nephrogenesis can be genetically substituted by Bmp4. Therefore, we investigated whether BMP7 in turn also participates in inhibiting ureteric bud outgrowth during the initiation of metanephric kidney development.
METHODOLOGY/PRINCIPAL FINDINGS: Genetic inactivation of one Bmp7 allele in Grem1-deficient mouse embryos does not alleviate the bilateral renal agenesis, while complete inactivation of Bmp7 restores ureteric bud outgrowth and branching. In mouse embryos lacking both Grem1 and Bmp7, GDNF/WNT11 feedback signaling and the expression of the Etv4 target gene, which regulates formation of the invading ureteric bud tip, are restored. In contrast to the restoration of ureteric bud outgrowth and branching, nephrogenesis remains aberrant as revealed by the premature loss of Six2 expressing nephrogenic progenitor cells. Therefore, very few nephrons develop in kidneys lacking both Grem1 and Bmp7 and the resulting dysplastic phenotype is indistinguishable from the one of Bmp7-deficient mouse embryos.
CONCLUSIONS/SIGNIFICANCE: Our study reveals an unexpected inhibitory role of BMP7 during the onset of ureteric bud outgrowth. As BMP4, BMP7 and GREM1 are expressed in distinct mesenchymal and epithelial domains, the localized antagonistic interactions of GREM1 with BMPs could restrict and guide ureteric bud outgrowth and branching. The robustness and likely significant redundancy of the underlying signaling system is evidenced by the fact that global reduction of Bmp4 or inactivation of Bmp7 are both able to restore ureteric bud outgrowth and epithelial branching in Grem1-deficient mouse embryos.
在小鼠中的基因分析表明，GREMLIN1（Grem1）介导的 BMP4 拮抗作用对于输尿管上皮分支至关重要，因为 Grem1 缺陷胚胎中输尿管芽生长的破坏和肾脏发育不全可以通过另一个 Bmp4 等位基因的失活来恢复。另一种 BMP 配体 BMP7 被证明可以控制肾祖细胞的增殖扩张，其对肾发生的需求可以通过 Bmp4 遗传替代。因此，我们研究了 BMP7 是否反过来也参与了在后肾原基发育开始时抑制输尿管芽生长。
方法/主要发现：在 Grem1 缺陷小鼠胚胎中遗传失活一个 Bmp7 等位基因不能缓解双侧肾脏发育不全，而完全失活 Bmp7 则恢复输尿管芽生长和分支。在缺乏 Grem1 和 Bmp7 的小鼠胚胎中，GDNF/WNT11 反馈信号和 Etv4 靶基因的表达得到恢复，该基因调控侵入性输尿管芽尖端的形成。与输尿管芽生长和分支的恢复相反，肾发生仍然异常，表现为 Six2 表达的肾祖细胞过早丢失。因此，在缺乏 Grem1 和 Bmp7 的肾脏中很少有肾单位发育，并且由此产生的发育不良表型与 Bmp7 缺陷小鼠胚胎的表型无法区分。
结论/意义：我们的研究揭示了 BMP7 在输尿管芽生长开始时的意外抑制作用。由于 BMP4、BMP7 和 Grem1 都在不同的间质和上皮区域表达，因此 Grem1 与 BMPs 的局部拮抗相互作用可以限制和指导输尿管芽的生长和分支。Bmp4 的全局减少或 Bmp7 的失活都能够恢复 Grem1 缺陷小鼠胚胎中的输尿管芽生长和上皮分支，这证明了潜在信号系统的稳健性和可能的显著冗余性。
