MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm.
MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm.
复制标题
DOI：
10.1002/dvdy.22477
复制
发表时间：
2011-03
影响因子：
2.5
通讯作者：
Holdener, Bernadette C.
中科院分区：
文献类型：
--
作者：
Lighthouse, Janet K.;Zhang, Liqun;Hsieh, Jen-Chih;Rosenquist, Thomas;Holdener, Bernadette C.
关键词：
Mesd基因区域的缺失阻断小鼠原肠胚形成和中胚层分化。MESD是Wnt共受体：低密度脂蛋白受体相关蛋白（LRP） 5和6 （LRP5/6）的伴侣。我们假设Wnt信号的缺失是Mesd缺陷胚胎中观察到的极性缺陷的原因。然而，由于Mesd缺陷胚胎比Lrp5/6或Wnt3突变体小得多，我们预测Mesd功能更广泛地扩展到LRP受体家族。与这一预测一致，我们证明体外MESD功能对于lrp共有的β-螺旋桨/EGF结构域的成熟至关重要。为了开始了解MESD在体内LRP成熟中的作用，我们进行了MESD的靶向敲除，并验证了MESD的缺失在体内阻断了WNT信号传导。Mesd突变体继续表达多能性标记物Oct4、Nanog和Sox2，这表明Wnt信号对于外胚层的分化至关重要。此外，我们证明了MESD对于内脏内胚层中相关LRP2 （Megalin/MEG）的顶端定位至关重要，从而导致内吞功能受损。综上所述，我们的研究结果提供了MESD作为一般LRP伴侣的证据，并表明MESD表型是由多个LRP受体错误折叠导致的信号传导和内吞缺陷引起的。
Deletion of the Mesd gene region blocks gastrulation and mesoderm differentiation in mice. MESD is a chaperone for the Wnt co-receptors: low-density lipoprotein receptor-related protein (LRP) 5 and 6 (LRP5/6). We hypothesized that loss of Wnt signaling is responsible for the polarity defects observed in Mesd deficient embryos. However, because the Mesd deficient embryo is considerably smaller than Lrp5/6 or Wnt3 mutants, we predicted that MESD function extends more broadly to the LRP family of receptors. Consistent with this prediction, we demonstrated that MESD function in vitro was essential for maturation of the β-propeller/EGF domain common to LRPs. To begin to understand the role of MESD in LRP maturation in vivo, we generated a targeted Mesd knockout and verified that loss of Mesd blocks WNT signaling in vivo. Mesd mutants continue to express pluripotency markers, Oct4, Nanog, and Sox2, suggesting that Wnt signaling is essential for differentiation of the epiblast. Moreover, we demonstrated that MESD was essential for the apical localization of the related LRP2 (Megalin/MEG) in the visceral endoderm, resulting in impaired endocytic function. Combined, our results provide evidence that MESD functions as a general LRP chaperone, and suggest that the Mesd phenotype results from both signaling and endocytic defects resulting from mis-folding of multiple LRP receptors.
登录
查看更多内容
影响因子：
13.6
作者：
Birn, H;Vorum, H;Christensen, EI
通讯作者：
Christensen, EI
影响因子：
64.5
作者：
Culi, J;Mann, RS
通讯作者：
Mann, RS
影响因子：
64.5
作者：
Hsieh, JC;Lee, L;Holdener, BC
通讯作者：
Holdener, BC
影响因子：
16
作者：
Fisher, C;Beglova, N;Blacklow, SC
通讯作者：
Blacklow, SC
影响因子：
4.6
作者：
Artus, Jerome;Panthier, Jean-Jacques;Hadjantonakis, Anna-Katerina
通讯作者：
Hadjantonakis, Anna-Katerina