Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons.
Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons.
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DOI：
10.1523/jneurosci.1445-09.2009
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发表时间：
2009-06-10
期刊：
影响因子：
--
通讯作者：
Kuruvilla R
中科院分区：
文献类型：
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作者：
Bodmer D;Levine-Wilkinson S;Richmond A;Hirsh S;Kuruvilla R
神经生长因子（NGF）是周围神经系统中神经元群体的有效存活和轴突生长因子。虽然靶源性NGF影响神经支配神经元存活的机制已被广泛研究，但其对轴突生长和靶神经支配的调节才刚刚阐明。在这里，我们确定Wnt 5a，分泌生长因子的Wnt家族的成员，作为一个关键的下游效应的神经生长因子在介导轴突分支和发展中的交感神经元的生长。当交感神经元的轴突支配表达NGF的靶标时，Wnt 5a在交感神经元中稳健地表达。NGF：TrkA信号传导增强Wnt 5a的神经元表达。wnt 5a快速诱导轴突分支，同时对促进轴突延伸具有长期作用。Wnt 5a功能的丧失表明，它是必要的神经生长因子依赖性轴突分支和生长，但不是生存，在体外。此外，Wnt 5a −/−小鼠体内显示表达NGF的靶组织的神经支配减少，随后神经元凋亡增加。Wnt 5a通过局部激活轴突中的蛋白激酶C（PKC）在发育交感神经元中起作用。总之，我们的研究结果定义了一种新的调节途径，其中Wnt 5a，在交感神经元中表达，响应于靶源性NGF，调节外周靶点的神经支配。
Nerve growth factor (NGF) is a potent survival and axon growth factor for neuronal populations in the peripheral nervous system. While the mechanisms by which target-derived NGF influences survival of innervating neurons have been extensively investigated, its regulation of axonal growth and target innervation are just being elucidated. Here, we identify Wnt5a, a member of the Wnt family of secreted growth factors, as a key downstream effector of NGF in mediating axonal branching and growth in developing sympathetic neurons. Wnt5a is robustly expressed in sympathetic neurons when their axons are innervating NGF-expressing targets. NGF:TrkA signaling enhances neuronal expression of Wnt5a. Wnt5a rapidly induces axon branching while it has a long-term effect on promoting axon extension. Loss of Wnt5a function revealed that it is necessary for NGF-dependent axonal branching and growth, but not survival, in vitro. Furthermore, Wnt5a−/− mice display reduced innervation of NGF-expressing target tissues, and a subsequent increase in neuronal apoptosis, in vivo. Wnt5a functions in developing sympathetic neurons by locally activating protein kinase C (PKC) in axons. Together, our findings define a novel regulatory pathway in which Wnt5a, expressed in sympathetic neurons in response to target-derived NGF, regulates innervation of peripheral targets.