Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis |
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Authors: | Nie Xuguang Xu Jinshu El-Hashash Ahmed Xu Pin-Xian |
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Institution: | aDepartment of Genetics and Genomic Sciences, Mount Sinai School of Medicine of NYU, New York, NY10029, USA;bDevelopmental and Regenerative Biology, Mount Sinai School of Medicine of NYU, New York, NY10029, USA |
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Abstract: | 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. |
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Keywords: | SIX1 Gremlin1 BMP4 Ureteric bud Ampulla |
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