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The Journal of Neuroscience, June 10, 2009, 29(23):7569-7581; doi:10.1523/JNEUROSCI.1445-09.2009

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Development/Plasticity/Repair
Wnt5a Mediates Nerve Growth Factor-Dependent Axonal Branching and Growth in Developing Sympathetic Neurons

Daniel Bodmer, ^* Seamus Levine-Wilkinson, ^* Alissa Richmond, Sarah Hirsh, and Rejji Kuruvilla

Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218

Correspondence should be addressed to Rejji Kuruvilla, Department of Biology, The Johns Hopkins University, Baltimore, MD 21218. Email: rkuruvilla{at}jhu.edu

Nerve growth factor (NGF) is a potent survival and axon growth factor for neuronal populations in the peripheral nervous system. Although 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 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.

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Received March 26, 2009; accepted May 6, 2009.

Correspondence should be addressed to Rejji Kuruvilla, Department of Biology, The Johns Hopkins University, Baltimore, MD 21218. Email: rkuruvilla{at}jhu.edu

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