Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling
Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling
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DOI：
10.1242/dev.085118
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发表时间：
2013-02-01
期刊：
影响因子：
4.6
通讯作者：
Krumlauf, Robb
中科院分区：
文献类型：
--
作者：
Ahn, Youngwook;Sims, Carrie;Krumlauf, Robb
在胚胎发生过程中，皮肤附属器发育的未来部位以基板为标志。尽管已知Wnt/β-连环蛋白信号传导对于皮肤附件发育是必不可少的，但尚不清楚哪些细胞过程由信号传导控制以及在基板形成期间如何实现信号传导活性的精确水平。我们研究了Lrp 4及其潜在配体Wise（Sostdc 1）在乳腺和其他皮肤附件基板中的作用。Lrp 4突变小鼠表现出基板启动延迟和乳腺前体细胞的分布和数量的变化，导致乳腺基板的形态、数量和位置异常。这些Lrp 4乳腺缺陷以及肢体缺陷与Wnt/β-连环蛋白信号传导升高相关，并通过减少Wnt共受体基因Lrp 5和Lrp 6的剂量或通过灭活编码β-连环蛋白的基因来挽救。Wise-null小鼠表型复制了Lrp 4乳腺缺陷的一个子集，Wise过表达减少了乳腺前体细胞的数量。遗传上位性分析表明，怀斯需要Lrp 4发挥其功能，并且它们一起在限制乳腺命运中发挥作用，但Lrp 4在促进基板形成中具有早期怀斯独立作用。Lrp 4和Wise突变体在触须和毛囊发育方面也有缺陷，这表明Lrp 4和Wise所起的作用对皮肤附件是共同的。我们的研究提供了Lrp 4和Wise在抑制Wnt/β-catenin信号传导方面相互作用的遗传证据，并深入了解了Wnt/β-catenin信号传导的调节如何控制对皮肤基板形成重要的细胞过程。
The future site of skin appendage development is marked by a placode during embryogenesis. Although Wnt/beta-catenin signaling is known to be essential for skin appendage development, it is unclear which cellular processes are controlled by the signaling and how the precise level of the signaling activity is achieved during placode formation. We have investigated roles for Lrp4 and its potential ligand Wise (Sostdc1) in mammary and other skin appendage placodes. Lrp4 mutant mice displayed a delay in placode initiation and changes in distribution and number of mammary precursor cells leading to abnormal morphology, number and position of mammary placodes. These Lrp4 mammary defects, as well as limb defects, were associated with elevated Wnt/beta-catenin signaling and were rescued by reducing the dose of the Wnt co-receptor genes Lrp5 and Lrp6, or by inactivating the gene encoding beta-catenin. Wise-null mice phenocopied a subset of the Lrp4 mammary defects and Wise overexpression reduced the number of mammary precursor cells. Genetic epistasis analyses suggest that Wise requires Lrp4 to exert its function and that, together, they have a role in limiting mammary fate, but Lrp4 has an early Wise-independent role in facilitating placode formation. Lrp4 and Wise mutants also share defects in vibrissa and hair follicle development, suggesting that the roles played by Lrp4 and Wise are common to skin appendages. Our study presents genetic evidence for interplay between Lrp4 and Wise in inhibiting Wnt/beta-catenin signaling and provides an insight into how modulation of Wnt/beta-catenin signaling controls cellular processes important for skin placode formation.