Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Development. 2018 Jul 9;145(13):dev159947. doi: 10.1242/dev.159947.
Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFβ2 signaling in -deficient mutants. We show that neutralization and knockdown of TGFβ2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of in stromal and nephrogenic cells results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in -deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFβ2 signaling axis acts to control nephrogenesis.
肾脏的功能单位。基质和肾祖细胞区之间的相互反馈信号相互作用被认为可以控制肾单位的发育。在这里，我们发现皮质基质中 hedgehog 细胞内效应蛋白 smoothened（-缺陷突变体）的缺失会导致肾脏包膜异常，并通过上皮化阻滞导致肾单位祖细胞域扩大，伴随肾单位数量减少。我们表明基质-hedgehog-Smo 信号通过 GLI3 抑制因子起作用。全肾 RNA 测序和 FACS 分离的基质细胞分析表明，-缺陷突变体中 TGFβ2 信号受损。我们表明，外植体中 TGFβ2 的中和和敲低抑制了肾发生。此外，我们证明在基质和肾原性细胞中同时缺失-导致肾单位形成减少和肾原性前体细胞域扩大，类似于在-缺陷突变体小鼠中观察到的情况。总之，我们的数据表明，基质 hedgehog-TGFβ2 信号轴通过控制肾发生起作用的机制。
