Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine of NYU, New York, NY 10029, USA.
Dev Biol. 2011 Apr 1;352(1):141-51. doi: 10.1016/j.ydbio.2011.01.027. Epub 2011 Jan 31.
Urinary tract morphogenesis requires subdivision of the ureteric bud (UB) into the intra-renal collecting system and the extra-renal ureter, by responding to signals in its surrounding mesenchyme. BMP4 is a mesenchymal regulator promoting ureter development, while GREM1 is necessary to negatively regulate BMP4 activity to induce UB branching. However, the mechanisms that regulate the GREM1-BMP4 signaling are unknown. Previous studies have shown that Six1-deficient mice lack kidneys, but form ureters. Here, we show that the tip cells of Six1(-/-) UB fail to form an ampulla for branching. Instead, the UB elongates within Tbx18- and Bmp4-expressing mesenchyme. We find that the expression of Grem1 in the metanephric mesenchyme (MM) is Six1-dependent. Treatment of Six1(-/-) kidney rudiments with GREM1 protein restores ampulla formation and branching morphogenesis. Furthermore, we demonstrate that genetic reduction of BMP4 levels in Six1(-/-) (Six1(-/-); Bmp4(+/-)) embryos restores urinary tract morphogenesis and kidney formation. This study uncovers an essential function for Six1 in the MM as an upstream regulator of Grem1 in initiating branching morphogenesis.
尿路上皮形态发生需要输尿管芽（UB）通过响应其周围间质中的信号来分为肾内收集系统和肾外输尿管，BMP4 是一种促进输尿管发育的间质调节剂，而 GREM1 则需要负向调节 BMP4 活性以诱导 UB 分支。然而，调节 GREM1-BMP4 信号的机制尚不清楚。先前的研究表明，Six1 缺陷型小鼠缺乏肾脏，但形成输尿管。在这里，我们表明 Six1(-/-)UB 的尖端细胞未能形成分支的壶腹。相反，UB 在 Tbx18 和 Bmp4 表达的间质中伸长。我们发现 Grem1 在肾间充质（MM）中的表达依赖于 Six1。用 GREM1 蛋白处理 Six1(-/-)肾原基可恢复壶腹形成和分支形态发生。此外，我们证明在 Six1(-/-)（Six1(-/-); Bmp4(+/-)）胚胎中遗传降低 BMP4 水平可恢复尿路上皮形态发生和肾脏形成。这项研究揭示了 Six1 在 MM 中作为启动分支形态发生的 Grem1 的上游调节剂的重要功能。
