Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis
Wnt5a-Ror-Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis
复制标题
DOI：
10.1073/pnas.1200421109
复制
发表时间：
2012-03-13
影响因子：
11.1
通讯作者：
Greenberg, Michael Eldon
中科院分区：
文献类型：
--
作者：
Ho, Hsin-Yi Henry;Susman, Michael W.;Greenberg, Michael Eldon
Wnt 构成了一个细胞外信号分子大家族，在发育和疾病中发挥着至关重要的作用。非经典 Wnt 的一个子集通过一种调节胚胎发生过程中关键形态发生运动的机制，独立于转录因子 β-catenin 发出信号。最具特征性的非经典 Wnt Wnt5a 被认为通过多种不同的受体发出信号，包括 Ror 受体酪氨酸激酶家族、Ryk 受体酪氨酸激酶和卷曲七次跨膜受体。这些受体中的一种或几种是否在体内介导 Wnt5a 的作用尚不清楚。通过小鼠功能丧失实验，我们提供了确凿的证据，证明 Ror 受体在体内介导 Wnt5a 依赖性过程，并将 Disheveled 磷酸化确定为 Wnt5a-Ror 信号传导的生理靶标。 Ror信号传导的缺失会导致与Wnt5a无效突变小鼠中观察到的表型相似的缺陷，包括交感神经元轴突分支减少以及依赖于形态发生运动的胚胎发育方面的主要缺陷，例如尾轴、四肢和面部结构的严重截断。这些发现表明，Wnt5a-Ror-Dishevelled 信号传导构成了核心的非经典 Wnt 通路，该通路在进化过程中是保守的，并且在胚胎发育过程中至关重要。
Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor beta-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a-Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a-Ror-Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.