Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program
Dosage-dependent hedgehog signals integrated with Wnt/β-catenin signaling regulate external genitalia formation as an appendicular program
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DOI：
10.1242/dev.039438
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发表时间：
2009-12-01
期刊：
影响因子：
4.6
通讯作者：
Yamada, Gen
中科院分区：
文献类型：
--
作者：
Miyagawa, Shinichi;Moon, Anne;Yamada, Gen
胚胎的附属结构，如肢芽和发育中的外生殖器，是分析生长因子在生长调节中的相互作用的合适模型。虽然一些研究已经评估了不同生长因子在细胞生长中的单独功能，但对来自多个信号级联的输入的协调功能和整合知之甚少。我们证明了一种新的信号级联控制胚胎外生殖器[生殖器结节（GT）]的形成。我们发现Shh信号的剂量与随后的Wnt/β-连环蛋白活性水平和外生殖器生长的程度密切相关。在Shh基因缺失的小鼠胚胎中，Wnt配体的表达和Wnt/β-连环蛋白信号传导活性均下调。β-连环蛋白功能获得性突变挽救Shh缺失胚胎中有缺陷的GT生长和Fgf 8表达这些数据表明，Wnt/β-连环蛋白信号在远端尿道上皮细胞的行为下游的Shh信号在GT生长。目前的数据还表明，Wnt/β-连环蛋白通过3'保守增强子中的Lef/Tcf结合位点调节Fgf 8表达。Fgf 8在体外诱导GT间充质中Erk 1/2的磷酸化和细胞增殖，但Fgf 4/8复合突变表型表明Fgf 4/8的功能不全，以及GT发育中多种Fgf之间冗余的可能性。我们的研究结果提供了新的见解，整合生长因子信号在apapperular发育程序，调节外生殖器的发展。
Embryonic appendicular structures, such as the limb buds and the developing external genitalia, are suitable models with which to analyze the reciprocal interactions of growth factors in the regulation of outgrowth. Although several studies have evaluated the individual functions of different growth factors in appendicular growth, the coordinated function and integration of input from multiple signaling cascades is poorly understood. We demonstrate that a novel signaling cascade governs formation of the embryonic external genitalia [genital tubercle (GT)]. We show that the dosage of Shh signal is tightly associated with subsequent levels of Wnt/beta-catenin activity and the extent of external genitalia outgrowth. In Shh-null mouse embryos, both expression of Wnt ligands and Wnt/beta-catenin signaling activity are downregulated. beta-catenin gain-of-function mutation rescues defective GT outgrowth and Fgf8 expression in Shh-null embryos. These data indicate that Wnt/beta-catenin signaling in the distal urethral epithelium acts downstream of Shh signaling during GT outgrowth. The current data also suggest that Wnt/beta-catenin regulates Fgf8 expression via Lef/Tcf binding sites in a 3' conserved enhancer. Fgf8 induces phosphorylation of Erk1/2 and cell proliferation in the GT mesenchyme in vitro, yet Fgf4/8 compound-mutant phenotypes indicate dispensable functions of Fgf4/8 and the possibility of redundancy among multiple Fgfs in GT development. Our results provide new insights into the integration of growth factor signaling in the appendicular developmental programs that regulate external genitalia development.