Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Dev Biol. 2013 May 1;377(1):79-89. doi: 10.1016/j.ydbio.2013.02.013. Epub 2013 Feb 27.
During nervous system development, axon branching at nerve terminals is an essential step in the formation of functional connections between neurons and target cells. It is known that target tissues exert control of terminal arborization through secretion of trophic factors. However, whether the in-growing axons themselves produce diffusible cues to instruct target innervation remains unclear. Here, we use conditional mutant mice to show that Wnt5a derived from sympathetic neurons is required for their target innervation in vivo. Conditional deletion of Wnt5a resulted in specific deficits in the extension and arborization of sympathetic fibers in their final target fields, while no defects were observed in the overall tissue patterning, proliferation, migration or differentiation of neuronal progenitors. Using compartmentalized neuronal cultures, we further demonstrate that the Ror receptor tyrosine kinases are required locally in sympathetic axons to mediate Wnt5a-dependent branching. Thus, our study suggests an autocrine Wnt5a-Ror signaling pathway that directs sympathetic axon branching during target innervation.
在神经系统发育过程中，神经末梢的轴突分支是神经元和靶细胞之间形成功能性连接的关键步骤。已知靶组织通过分泌营养因子来控制终末树突的分支。然而，向内生长的轴突本身是否产生扩散信号来指导靶神经支配尚不清楚。在这里，我们使用条件性突变小鼠表明，交感神经元衍生的 Wnt5a 对于它们在体内的靶神经支配是必需的。Wnt5a 的条件性缺失导致交感纤维在其最终靶场中的延伸和分支特异性缺陷，而在神经元祖细胞的整体组织模式、增殖、迁移或分化中没有观察到缺陷。使用分隔的神经元培养物，我们进一步证明，Ror 受体酪氨酸激酶在交感轴突中局部需要介导 Wnt5a 依赖性分支。因此，我们的研究表明，在靶神经支配过程中，自主 Wnt5a-Ror 信号通路指导交感轴突分支。
