Multiple roles of mesenchymal β-catenin during murine limb patterning
Multiple roles of mesenchymal β-catenin during murine limb patterning
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DOI：
10.1242/dev.02298
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发表时间：
2006-04-01
期刊：
影响因子：
4.6
通讯作者：
Hartmann, C
中科院分区：
文献类型：
--
作者：
Hill, TP;Taketo, MM;Hartmann, C
最近，外胚层中的经典 Wnt 信号传导已被证明是维持顶外胚层脊 (AER) 和背腹信号传导所必需的。利用条件获得和丧失功能的β-连环蛋白等位基因，我们研究了间充质β-连环蛋白活性在肢体发育过程中的作用。在这里，我们发现，由于 AER 维持缺陷，β-连环蛋白的缺失会导致肢体截断。 β-连环蛋白的稳定也会导致由于 AER 过早消退而导致的四肢截短。与此同时，在这些肢体中，Bmp2、Bmp4 和 Bmp7 以及 Bmp 靶基因 Msx1、Msx2 和 gremlin 的表达在间充质中扩增。此外，我们发现Lmx1b（一种专门在背侧肢体间充质中表达并参与背腹侧模式形成的基因）的表达在β-连环蛋白活性丧失时减少，并在功能获得性肢体中向腹侧扩展。然而，已知的外胚层调节因子 Wnt7a 和 engrailed 1 表达正常。这表明 Lmx1b 也部分受到 β-连环蛋白介导的 Wnt 信号的调节，独立于非经典的 Wnt7a 信号通路。此外，β-连环蛋白的缺失会导致肩胛骨严重发育不全。同时，与肩胛骨发育有关的两个基因Pax1和Emx2的表达在β-连环蛋白功能丧失的肢体中消失；然而，只有 Emx2 在功能获得肢体中上调。因此，间充质 β-连环蛋白活性是 AER 维持以及 Lmx1b 和 Emx2 正常表达所必需的。
Recently canonical Wnt signaling in the ectoderm has been shown to be required for maintenance of the apical ectodermal ridge (AER) and for dorsoventral signaling. Using conditional gain- and loss-of-function beta-catenin alleles, we have studied the role of mesenchymal beta-catenin activity during limb development. Here, we show that loss of beta-catenin results in limb truncations due to a defect in AER maintenance. Stabilization of beta-catenin also results in truncated limbs, caused by a premature regression of the AER. Concomitantly, in these limbs, the expression of Bmp2, Bmp4 and Bmp7, and of the Bmp target genes Msx1, Msx2 and gremlin, is expanded in the mesenchyme. Furthermore, we found that the expression of Lmx1b, a gene exclusively expressed in the dorsal limb mesenchyme and involved in dorsoventral patterning, is reduced upon loss of beta-catenin activity and is expanded ventrally in gain-of-function limbs. However, the known ectodermal regulators Wnt7a and engrailed 1 are expressed normally. This suggests that Lmx1b is also regulated, in part, by a beta-catenin-mediated Wnt signal, independent of the non-canoncial Wnt7a signaling pathway. In addition, loss of beta-catenin results in a severe agenesis of the scapula. Concurrently, the expression of two genes, Pax1 and Emx2, which have been implicated in scapula development, is lost in beta-catenin loss-of-function limbs; however, only Emx2 is upregulated in gain-of-function limbs. Mesenchymal beta-catenin activity is therefore required for AER maintenance, and for normal expression of Lmx1b and Emx2.