Iglesias Diana M, Hueber Pierre-Alain, Chu LeeLee, Campbell Robert, Patenaude Anne-Marie, Dziarmaga Alison J, Quinlan Jacklyn, Mohamed Othman, Dufort Daniel, Goodyer Paul R
Department of Human Genetics, McGill University-Montreal Children's Hospital Research Institute, 4060 St. Catherine West, Montreal, QC, Canada H3Z 2Z3.
Am J Physiol Renal Physiol. 2007 Aug;293(2):F494-500. doi: 10.1152/ajprenal.00416.2006. Epub 2007 May 9.
The canonical WNT signaling pathway plays a crucial role in patterning of the embryo during development, but little is known about the specific developmental events which are under WNT control. To understand more about how the WNT pathway orchestrates mammalian organogenesis, we studied the canonical beta-catenin-mediated WNT signaling pathway in kidneys of mice bearing a beta-catenin-responsive TCF/betaGal reporter transgene. In metanephric kidney, intense canonical WNT signaling was evident in epithelia of the branching ureteric bud and in nephrogenic mesenchyme during its transition into renal tubules. WNT signaling activity is rapidly downregulated in maturing nephrons and becomes undetectable in postnatal kidney. Sites of TCF/betaGal activity are in proximity to the known sites of renal WNT2b and WNT4 expression, and these WNTs stimulate TCF reporter activity in kidney cell lines derived from ureteric bud and metanephric mesenchyme lineages. When fetal kidney explants from HoxB7/GFP mice were exposed to the canonical WNT signaling pathway inhibitor, Dickkopf-1, arborization of the ureteric bud was significantly reduced. We conclude that restricted zones of intense canonical WNT signaling drive branching nephrogenesis in fetal kidney.
经典WNT信号通路在胚胎发育过程中的模式形成中起着关键作用，但对于WNT控制下的具体发育事件却知之甚少。为了更深入了解WNT信号通路如何协调哺乳动物器官发生，我们在携带β-连环蛋白反应性TCF/β半乳糖苷酶报告基因转基因的小鼠肾脏中研究了经典的β-连环蛋白介导的WNT信号通路。在中肾肾中，在分支输尿管芽的上皮以及肾发生间充质向肾小管转变过程中，明显存在强烈的经典WNT信号。WNT信号活性在成熟肾单位中迅速下调，在出生后肾脏中无法检测到。TCF/β半乳糖苷酶活性位点靠近已知的肾脏WNT2b和WNT4表达位点，并且这些WNT在源自输尿管芽和中肾间充质谱系的肾细胞系中刺激TCF报告基因活性。当将来自HoxB7/GFP小鼠的胎儿肾外植体暴露于经典WNT信号通路抑制剂Dickkopf-1时，输尿管芽的分支明显减少。我们得出结论，强烈的经典WNT信号的受限区域驱动胎儿肾脏中的分支肾发生。
