title: N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons.
abstract: Axonogenesis, 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.
authors.affiliation: 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.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Kharebava
authors.affiliation: 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.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Rashid
authors.affiliation: 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.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sarmila
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: 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.
authors.forename: Karl
authors.initials: K
authors.lastname: Kevala
authors.affiliation: 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 hykim@nih.gov.
authors.forename: Hee-Yong
authors.initials: HY
authors.lastname: Kim
keywords: Axon; Cyclopamine; Docosahexaenoic acid; Sonic hedgehog; Synaptamide