PDF(Pubmed)
Abstract：
Precise control of morphogen signaling levels is essential for proper development. An outstanding question is: what mechanisms ensure proper morphogen activity and correct cellular responses? Previous work has identified Semaphorin (SEMA) receptors, Neuropilins (NRPs) and Plexins (PLXNs), as positive regulators of the Hedgehog (HH) signaling pathway. Here, we provide evidence that NRPs and PLXNs antagonize Wnt signaling in both fibroblasts and epithelial cells. Further, Nrp1/2 deletion in fibroblasts results in elevated baseline Wnt pathway activity and increased maximal responses to Wnt stimulation. Notably, and in contrast to HH signaling, SEMA receptor-mediated Wnt antagonism is independent of primary cilia. Mechanistically, PLXNs and NRPs act downstream of Dishevelled (DVL) to destabilize β-catenin (CTNNB1) in a proteosome-dependent manner. Further, NRPs, but not PLXNs, act in a GSK3β/CK1-dependent fashion to antagonize Wnt signaling, suggesting distinct repressive mechanisms for these SEMA receptors. Overall, this study identifies SEMA receptors as novel Wnt pathway antagonists that may also play larger roles integrating signals from multiple inputs.
摘要：
对形态发生原信号水平的精确控制对于正常发育至关重要。一个突出的问题是：什么机制确保适当的形态发生活性和正确的细胞反应？以前的工作已经确定了信号素（SEMA）受体，神经菌毛蛋白（NRP）和神经丛蛋白（PLXNs），作为Hedgehog（HH）信号通路的正调节因子。这里,我们提供了NRP和PLXN拮抗成纤维细胞和上皮细胞中Wnt信号的证据.Further,成纤维细胞中的Nrp1/2缺失导致基线Wnt途径活性升高和对Wnt刺激的最大应答增加。值得注意的是,与HH信号相反，SEMA受体介导的Wnt拮抗作用与初级纤毛无关。机械上,PLXN和NRP在Dishevelled（DVL）的下游起作用，以蛋白酶体依赖性方式使β-catenin（CTNNB1）不稳定。Further,NRP,但不是PLXN，以GSK3b/CK1依赖性方式拮抗Wnt信号，提示这些SEMA受体不同的抑制机制。总的来说,这项研究将SEMA受体鉴定为新型Wnt通路拮抗剂,它们也可能在整合来自多个输入的信号方面发挥更大的作用.
