N-docosahexaenoylethanolamine regulates Hedgehog signaling and promotes growth of cortical axons

Giorgi Kharebava, Mohammad A. Rashid, Ji Won Lee, Sarmila Sarkar, Karl Kevala, Hee Yong Kim

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 (Ndocosahexaenoylethanolamine), 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, noncanonical pathway.

Original languageEnglish (US)
Pages (from-to)1660-1670
Number of pages11
JournalBiology Open
Issue number12
StatePublished - 2015

Bibliographical note

Funding Information:
This study was supported by the Defense Medical Research and Development Program (DMRDP) [W81XWH-11-2-0074] and Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

Publisher Copyright:
© 2015. Published by The Company of Biologists Ltd |.


  • Axon
  • Cyclopamine
  • Docosahexaenoic acid
  • Sonic hedgehog
  • Synaptamide

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