Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis
Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis
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DOI：
10.1242/dev.01405
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发表时间：
2004-11-01
期刊：
影响因子：
4.6
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Kokubu, C;Heinzmann, U;Imai, K
在这里，我们提出的证据表明，Lrp 6，Wnt配体的辅助受体，体节和骨骼的正常形成所需的。通过定位克隆，我们证明了一种新的自发突变ringelschwanz（rs）在小鼠中是由Lrp 6的点突变，导致氨基酸取代色氨酸的进化保守残基精氨酸在密码子886（R886 W）。我们表明，rs是一个亚型Lrp 6等位基因与Lrp 6基因缺失小鼠的遗传互补测试，突变的蛋白质不能有效地通过Wnt/β-连环蛋白途径的信号转导。纯合子rs小鼠，其中许多是非常可行的，表现出多种Wnt缺陷的表型，包括轴骨，手指和神经管的畸形的组合。在rs突变体中，前后体节间室的建立、新生体节的上皮化和体节边界的形成受到干扰，导致脊椎畸形的特征形式，类似于脊椎肋骨发育不全患者的畸形。标记物表达研究表明，Lrp 6是必需的Wnt和notch-delta信号通路之间的串扰在体节发生。此外，rs中的Lrp 6功能障碍导致出生时骨化延迟和成人低骨量表型。总之，我们认为Lrp 6是人类脊椎分割缺陷和骨质疏松症发病机制的关键遗传成分之一。
Here, we present evidence that Lrp6, a coreceptor for Wnt ligands, is required for the normal formation of somites and bones. By positional cloning, we demonstrate that a novel spontaneous mutation ringelschwanz (rs) in the mouse is caused by a point mutation in Lrp6, leading to an amino acid substitution of tryptophan for the evolutionarily conserved residue arginine at codon 886 (R886W). We show that rs is a hypomorphic Lrp6 allele by a genetic complementation test with Lrp6-null mice, and that the mutated protein cannot efficiently transduce signals through the Wnt/beta-catenin pathway. Homozygous rs mice, many of which are remarkably viable, exhibit a combination of multiple Wnt-deficient phenotypes, including dysmorphologies of the axial skeleton, digits and the neural tube. The establishment of the anteroposterior somite compartments, the epithelialization of nascent somites, and the formation of segment borders are disturbed in rs mutants, leading to a characteristic form of vertebral malformations, similar to dysmorphologies in individuals suffering from spondylocostal dysostosis. Marker expression study suggests that Lrp6 is required for the crosstalk between the Wnt and notch-delta signaling pathways during somitogenesis. Furthermore, the Lrp6 dysfunction in rs leads to delayed ossification at birth and to a low bone mass phenotype in adults. Together, we propose that Lrp6 is one of the key genetic components for the pathogenesis of vertebral segmentation defects and of osteoporosis in humans.