Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization

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Abstract
Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis. The molecular signaling cascade underlying this event remains obscure. Through Ca2+ imaging in acute embryonic cortical slices, we tested if radially migrating cortical excitatory neurons that already bore primitive axons were sensitive to Wnt5a. While Wnt5a only evoked brief Ca2+ transients in immature neurons present in the intermediate zone (IZ), Wnt5a-induced Ca2+ oscillations were sustained in neurons that migrated out to the cortical plate (CP). We wondered whether this early Wnt5a-Ca2+ signaling during neuronal polarization has a morphogenetic consequence. During transition from round to polarized shape, Wnt5a administration to immature cultured cortical neurons specifically promoted axonal, but not dendritic, outgrowth. Pharmacological and genetic inhibition of the CaMKK-CaMKIα pathway abolished Wnt5a-induced axonal elongation, and rescue of CaMKIα in CaMKIα-knockdown neurons restored Wnt5a-mediated axon outgrowth. This study suggests that Wnt5a activates Ca2+ signaling during a neuronal morphogenetic time window when axon outgrowth is critically facilitated. Furthermore, the CaMKK-CaMKIα cascade is required for the axonal growth effect of Wnt5a during neuronal polarization.
Funding Information
  • Japan Society for the Promotion of Science (26440095, 15H02358)
  • AMED (CREST)
  • Japan Science and Technology Agency (PRESTO)
  • Narishige Neuroscience Research Foundation
  • Sumitomo Foundation
  • Astellas Foundation for Research on Metabolic Disorders
  • Japan Foundation for Applied Enzymology
  • Takeda Science Foundation

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