Wnt5a mediates nerve growth factor-dependent axonal branching and growth in developing sympathetic neurons.
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.
Bodmer
Daniel
D
Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Levine-Wilkinson
Seamus
S
Richmond
Alissa
A
Hirsh
Sarah
S
Kuruvilla
Rejji
R
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D011493:Protein Kinase C