Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B.
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DOI：
10.1093/hmg/ddq462
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发表时间：
2011-01
影响因子：
3.5
通讯作者：
Bing Wang;Tanvi Sinha;K. Jiao;R. Serra;Jianbo Wang
中科院分区：
文献类型：
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作者：
Bing Wang;Tanvi Sinha;K. Jiao;R. Serra;Jianbo Wang
B 型短指畸形 (BDB1) 和 Robinow 综合征 (RRS) 是由 Wnt5a 共同受体 ROR2 突变引起的两种骨骼疾病。 Wnt5a/Ror2 可以激活非经典 Wnt 信号传导的多个分支，但尚不清楚哪个分支在肢体骨骼发育中介导 Wnt5a/Ror2 功能。在这里，我们提供的证据表明平面细胞极性（PCP）通路是肢体中 Wnt5a 的下游组成部分。我们发现，小鼠 PCP 基因 Vangl2 的突变会导致类似于 BDB1 临床表型的手指缺陷，包括指骨缺失。将 Vangl2 突变体中 Wnt5a 的剂量减半会增强手指缺损的严重程度和外显率，并导致让人想起 RRS 的长骨缺损，这表明 Wnt5a 和 Vangl2 在同一途径中发挥作用，PCP 信号传导的破坏可能是 BDB1 和 RRS 的基础。与 PCP 信号在组织形态发生中的作用一致，Vangl2 的突变改变了早期肢芽的形状和尺寸：宽度和厚度增加，而长度减少。手指前软骨形成凝结物也变得更宽、更粗和更短。有趣的是，Vangl2 突变体中肢芽尺寸的改变也会通过扰乱调节 Fgf 和 Bmp 信号之间平衡的信号网络来影响肢体生长。将 Bmp4 的剂量减半可部分抑制 Vangl2 突变体中指骨的丢失，这支持了以下假设：Bmp 信号传导的异常增加是短指缺陷的原因。这些发现为 Wnt5a/Ror2 的信号传导机制以及 BDB1 和 RRS 的发病机制提供了新的见解。
Brachydactyly type B (BDB1) and Robinow syndrome (RRS) are two skeletal disorders caused by mutations in ROR2, a co-receptor of Wnt5a. Wnt5a/Ror2 can activate multiple branches of non-canonical Wnt signaling, but it is unclear which branch(es) mediates Wnt5a/Ror2 function in limb skeletal development. Here, we provide evidence implicating the planar cell polarity (PCP) pathway as the downstream component of Wnt5a in the limb. We show that a mutation in the mouse PCP gene Vangl2 causes digit defects resembling the clinical phenotypes in BDB1, including loss of phalanges. Halving the dosage of Wnt5a in Vangl2 mutants enhances the severity and penetrance of the digit defects and causes long bone defects reminiscent of RRS, suggesting that Wnt5a and Vangl2 function in the same pathway and disruption of PCP signaling may underlie both BDB1 and RRS. Consistent with a role for PCP signaling in tissue morphogenesis, mutation of Vangl2 alters the shape and dimensions of early limb buds: the width and thickness are increased, whereas the length is decreased. The digit pre-chondrogenic condensates also become wider, thicker and shorter. Interestingly, altered limb bud dimensions in Vangl2 mutants also affect limb growth by perturbing the signaling network that regulates the balance between Fgf and Bmp signaling. Halving the dosage of Bmp4 partially suppresses the loss of phalanges in Vangl2 mutants, supporting the hypothesis that an aberrant increase in Bmp signaling is the cause of the brachydactyly defect. These findings provide novel insight into the signaling mechanisms of Wnt5a/Ror2 and the pathogenesis in BDB1 and RRS.