Abstract
ABSTRACTAxonogenesis, a process for the establishment of neuron connectivity, is central to brain function. The role of metabolites derived from docosahexaenoic acid (DHA, 22:6n-3) that is specifically enriched in the brain, has not been addressed in axon development. In this study, we tested if synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of DHA, affects axon growth in cultured cortical neurons. We found that synaptamide increased the average axon length, inhibited GLI family zinc finger 1 (GLI1) transcription and sonic hedgehog (Shh) target gene expression while inducing cAMP elevation. Similar effects were produced by cyclopamine, a regulator of the Shh pathway. Conversely, Shh antagonized elevation of cAMP and blocked synaptamide-mediated increase in axon length. Activation of Shh pathway by a smoothened (SMO) agonist (SAG) or overexpression of SMO did not inhibit axon growth mediated by synaptamide or cyclopamine. Instead, adenylate cyclase inhibitor SQ22536 abolished synaptamide-mediated axon growth indicating requirement of cAMP elevation for this process. Our findings establish that synaptamide promotes axon growth while Shh antagonizes synaptamide-mediated cAMP elevation and axon growth by a SMO-independent, non-canonical pathway.
Highlights
Axon development is regulated by precisely timed and spaced interactions between extrinsic cues and intrinsic mechanisms
Supplementation of synaptamide at a concentration of 100 nM for 48 h increased average axon length of the cortical neurons by 25% (P=0.0001 vs vehicle) (Fig. 1A,B)
To test if synaptamide can trigger signaling associated with axon development, we evaluated Ser-41 phosphorylation of growth associated protein 43 (GAP43)
Summary
Axon development is regulated by precisely timed and spaced interactions between extrinsic cues and intrinsic mechanisms. This process includes axon specification, growth and guidance, which are crucial for establishing proper brain circuitry. Laboratory of Molecular Signaling, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20852, USA. Numerous studies have indicated that many extracellular signals modulate cyclic adenosine monophosphate (cAMP) levels to promote initiation and growth of axons (Cheng et al, 2011; Corredor et al, 2012; Rydel and Greene, 1988; Shelly et al, 2010).
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