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首页> 外文期刊>Development >Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis.
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Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis.

机译：Ringelschwanz突变小鼠的骨骼缺损显示Lrp6是正常的骨形成和成骨作用所必需的。

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摘要

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.
机译：在这里，我们提供证据表明Lnt6，Wnt配体的共受体，是正常形成的节节和骨骼所必需的。通过位置克隆，我们证明了小鼠中的新的自发突变ringelschwanz（rs）是由Lrp6中的点突变引起的，导致色氨酸被氨基酸替换为886号密码子（R886W）上的保守保守残基。我们通过与Lrp6-null小鼠的基因互补测试显示rs是亚型Lrp6等位基因，并且突变蛋白不能有效地通过Wnt /β-catenin途径转导信号。纯合子rs小鼠，其中许多是非常有生存力的，表现出多种Wnt缺陷表型的组合，包括轴向骨骼，手指和神经管的畸形。在rs突变体中，前后体节室的建立，新生体的上皮形成和节段边界的形成受到干扰，从而导致了脊椎畸形的特征形式，类似于患有脊椎肋骨异位症的个体的畸形。标记表达研究表明，在体发生过程中，Wnt和notch-delta信号通路之间的串扰需要Lrp6。此外，rs中的Lrp6功能障碍导致出生时骨化延迟和成人骨质表型降低。在一起，我们建议Lrp6是人类椎骨节段缺损和骨质疏松症发病机理的关键遗传成分之一。

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