Yu Jing, Carroll Thomas J, McMahon Andrew P
Department of Molecular and Cellular Biology, 16 Divinity Avenue, Harvard University, Cambridge MA 02138, USA.
Development. 2002 Nov;129(22):5301-12. doi: 10.1242/dev.129.22.5301.
Signaling by the ureteric bud epithelium is essential for survival, proliferation and differentiation of the metanephric mesenchyme during kidney development. Most studies that have addressed ureteric signaling have focused on the proximal, branching, ureteric epithelium. We demonstrate that sonic hedgehog is expressed in the ureteric epithelium of the distal, non-branching medullary collecting ducts and continues into the epithelium of the ureter -- the urinary outflow tract that connects the kidney with the bladder. Upregulation of patched 1, the sonic hedgehog receptor and a downstream target gene of the signaling pathway in the mesenchyme surrounding the distal collecting ducts and the ureter suggests that sonic hedgehog acts as a paracrine signal. In vivo and in vitro analyses demonstrate that sonic hedgehog promotes mesenchymal cell proliferation, regulates the timing of differentiation of smooth muscle progenitor cells, and sets the pattern of mesenchymal differentiation through its dose-dependent inhibition of smooth muscle formation. In addition, we also show that bone morphogenetic protein 4 is a downstream target gene of sonic hedgehog signaling in kidney stroma and ureteral mesenchyme, but does not mediate the effects of sonic hedgehog in the control of mesenchymal proliferation.
在肾脏发育过程中，输尿管芽上皮发出的信号对于后肾间充质的存活、增殖和分化至关重要。大多数研究输尿管信号传导的研究都集中在近端、分支的输尿管上皮。我们证明，音猬因子在远端、非分支的髓质集合管的输尿管上皮中表达，并延续到输尿管的上皮中——输尿管是连接肾脏和膀胱的尿液流出通道。在远端集合管和输尿管周围的间充质中，音猬因子受体patched 1（信号通路的一个下游靶基因）的上调表明音猬因子作为旁分泌信号发挥作用。体内和体外分析表明，音猬因子促进间充质细胞增殖，调节平滑肌祖细胞的分化时间，并通过其对平滑肌形成的剂量依赖性抑制来设定间充质分化模式。此外，我们还表明，骨形态发生蛋白4是肾脏基质和输尿管间充质中音猬因子信号传导的下游靶基因，但不介导音猬因子在控制间充质增殖方面的作用。
