Bian Wen-Jie, Miao Wan-Ying, He Shun-Ji, Wan Zong-Fang, Luo Zhen-Ge, Yu Xiang
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
University of Chinese Academy of Sciences, Shanghai, 200031, China.
Dev Neurobiol. 2015 Aug;75(8):805-22. doi: 10.1002/dneu.22250. Epub 2014 Dec 1.
The morphology of the dendritic tree is critical to neuronal function and neural circuit wiring. Several Wnt family members have been demonstrated to play important roles in dendrite development. However, the Wnt receptors responsible for mediating this process remain largely elusive. Using primary hippocampal neuronal cultures as a model system, we report that Frizzled4 (Fzd4), a member of the Fzd family of Wnt receptors, specifically signals downstream of Wnt5a to promote dendrite branching and growth. Interestingly, the less conserved distal PDZ binding motif of Fzd4, and not its conserved proximal Dvl-interacting PDZ motif, is required for mediating this effect. We further showed that Dvl signaled parallel to and independent of Fzd4 in promoting dendrite growth. Unlike most previously described pathways, Wnt5a/Fzd4 signaling promoted dendrite development in an activity-independent and autocrine fashion. Together, these results provide the first identification of a Wnt receptor for regulating dendrite development in the mammalian system, and demonstrate a novel function of the distal PDZ motif of Fzd4 in dendrite morphogenesis, thereby expanding our knowledge of the complex roles of Wnt signaling in neural development.
树突状树的形态对于神经元功能和神经回路布线至关重要。已证实多个Wnt家族成员在树突发育中发挥重要作用。然而,介导这一过程的Wnt受体在很大程度上仍不清楚。我们以原代海马神经元培养物作为模型系统,报告称Wnt受体Fzd家族的成员卷曲蛋白4(Fzd4)特异性地在Wnt5a下游发出信号,以促进树突分支和生长。有趣的是,介导这种效应需要Fzd4中保守性较低的远端PDZ结合基序,而不是其保守的近端与Dvl相互作用的PDZ基序。我们进一步表明,在促进树突生长方面,Dvl与Fzd4平行且独立地发出信号。与大多数先前描述的途径不同,Wnt5a/Fzd4信号以与活性无关的自分泌方式促进树突发育。总之,这些结果首次鉴定出一种在哺乳动物系统中调节树突发育的Wnt受体,并证明了Fzd4的远端PDZ基序在树突形态发生中的新功能,从而扩展了我们对Wnt信号在神经发育中复杂作用的认识。