Abstract
BackgroundWnt5a, 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.ResultsThrough 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0189-3) contains supplementary material, which is available to authorized users.
Highlights
Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis
Combining Fluo-4 Ca2+ imaging and in utero electroporation in acute embryonic cortical slices, we tested if radially migrating cortical excitatory neurons that already bore primitive axons were sensitive to Wnt5a
Through a morphogenetic process that occurs in parallel to the determination neuronal cell polarity, most neurons begin to grow axons in intermediate zone (IZ) and extend them while they radially migrate into cortical plate (CP) towards the pial surface [1, 23]
Summary
Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis. Wnt proteins are highly conserved, secreted morphogens that activate the βcatenin-mediated canonical pathway as well as planar cell polarity and Ca2+-mediated non-canonical signaling pathways [2, 3]. In addition to their primary functions during the early developmental stages, Wnt proteins have been shown to regulate the cerebral cortex throughout development during various morphogenetic processes, such as anterior–posterior axis formation, One of the most extensively studied Wnt proteins is Wnt5a. Wnt5a activates a non-canonical Wnt pathway that is conserved from Caenorhabditis elegans to humans and regulates a variety of cellular functions [6].
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