Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.
Syndecan 4 interacts genetically with Vangl2 to regulate neural tube closure and planar cell polarity.
复制标题
DOI：
10.1242/dev.091173
复制
发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Larraín J
中科院分区：
文献类型：
--
作者：
Escobedo N;Contreras O;Muñoz R;Farías M;Carrasco H;Hill C;Tran U;Pryor SE;Wessely O;Copp AJ;Larraín J
Syndecan 4 (Sdc4) 是一种细胞表面硫酸乙酰肝素蛋白聚糖 (HSPG)，可调节非洲爪蟾发育中的原肠胚形成、神经管闭合和定向神经嵴迁移。为了确定 Sdc4 是否参与小鼠发育过程中的 Wnt/PCP 信号传导，我们评估了 Sdc4 的无效突变与 Vangl2 环尾等位基因之间可能的相互作用。 Sdc4 在多种组织中表达，特别是在非神经外胚层、后肠和耳囊中。 Sdc4;Vangl2Lp 复合突变小鼠具有缺陷的脊髓神经管闭合、耳蜗中静纤毛束的方向被破坏以及伤口愈合延迟，这表明了强烈的遗传相互作用。在非洲爪蟾中，联合注射次优量的 Sdc4 和 Vangl2 吗啉会导致神经管闭合缺陷胚胎的比例显着高于单独注射吗啉。为了探究这种相互作用的机制，我们在 HEK293 细胞中过表达或敲低 Vangl2 功能。 Sdc4 和 Vangl2 蛋白共定位，Vangl2（特别是 Vangl2Lp 突变体形式）会降低 Sdc4 蛋白水平。相反，Vangl2 敲低会增强 Sdc4 蛋白水平。总体 HSPG 稳态水平受 Vangl2 调节，这表明 Vangl2Lp/+ 增强 Sdc4-null 表型的遗传相互作用的分子机制。这可能是通过硫酸乙酰肝素残基介导的，因为当在硫酸盐抑制剂氯酸盐存在下培养时，Vangl2Lp/+ 胚胎无法启动神经管闭合并发生颅骨劈裂（通常仅在 Vangl2Lp/Lp 中看到）。这些结果表明 Sdc4 可以参与 Wnt/PCP 途径，揭示了其在哺乳动物胚胎神经管闭合过程中的重要性。
Syndecan 4 (Sdc4) is a cell-surface heparan sulfate proteoglycan (HSPG) that regulates gastrulation, neural tube closure and directed neural crest migration in Xenopus development. To determine whether Sdc4 participates in Wnt/PCP signaling during mouse development, we evaluated a possible interaction between a null mutation of Sdc4 and the loop-tail allele of Vangl2. Sdc4 is expressed in multiple tissues, but particularly in the non-neural ectoderm, hindgut and otic vesicles. Sdc4;Vangl2Lp compound mutant mice have defective spinal neural tube closure, disrupted orientation of the stereocilia bundles in the cochlea and delayed wound healing, demonstrating a strong genetic interaction. In Xenopus, co-injection of suboptimal amounts of Sdc4 and Vangl2 morpholinos resulted in a significantly greater proportion of embryos with defective neural tube closure than each individual morpholino alone. To probe the mechanism of this interaction, we overexpressed or knocked down Vangl2 function in HEK293 cells. The Sdc4 and Vangl2 proteins colocalize, and Vangl2, particularly the Vangl2Lp mutant form, diminishes Sdc4 protein levels. Conversely, Vangl2 knockdown enhances Sdc4 protein levels. Overall HSPG steady-state levels were regulated by Vangl2, suggesting a molecular mechanism for the genetic interaction in which Vangl2Lp/+ enhances the Sdc4-null phenotype. This could be mediated via heparan sulfate residues, as Vangl2Lp/+ embryos fail to initiate neural tube closure and develop craniorachischisis (usually seen only in Vangl2Lp/Lp) when cultured in the presence of chlorate, a sulfation inhibitor. These results demonstrate that Sdc4 can participate in the Wnt/PCP pathway, unveiling its importance during neural tube closure in mammalian embryos.
登录
查看更多内容
影响因子：
64.8
作者：
Lu, XW;Borchers, AGM;Tessier-Lavigne, M
通讯作者：
Tessier-Lavigne, M
影响因子：
2.9
作者：
Iliescu, Alexandra;Gravel, Michel;Gros, Philippe
通讯作者：
Gros, Philippe
影响因子：
4.8
作者：
Ishiguro, K;Kadomatsu, K;Muramatsu, T
通讯作者：
Muramatsu, T
影响因子：
158.5
作者：
Kibar, Zoha;Torban, Elena;Gros, Philippe
通讯作者：
Gros, Philippe
影响因子：
23.9
作者：
Bentzinger, C. Florian;Wang, Yu Xin;von Maltzahn, Julia;Soleimani, Vahab D.;Yin, Hang;Rudnicki, Michael A.;Rudnicki, A.
通讯作者：
Rudnicki, A.