Growth of neurite processes from the cell body is the critical step in neuronal development and involves a large increase in cell membrane surface area1. Arachidonic-acid-releasing phospholipases are highly enriched in nerve growth cones and have previously been implicated in neurite outgrowth2,3. Cell membrane expansion is achieved through the fusion of transport organelles with the plasma membrane4; however, the identity of the molecular target of arachidonic acid has remained elusive. Here we show that syntaxin 3 (STX3), a plasma membrane protein, has an important role in the growth of neurites, and also serves as a direct target for omega-6 arachidonic acid. By using syntaxin 3 in a screening assay, we determined that the dietary omega-3 linolenic and docosahexaenoic acids can efficiently substitute for arachidonic acid in activating syntaxin 3. Our findings provide a molecular basis for the previously established action of omega-3 and omega-6 polyunsaturated fatty acids in membrane expansion at the growth cones, and represent the first identification of a single effector molecule for these essential nutrients.
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We thank A. Derevier for neuronal cultures. F.D. was supported by an EMBO long-term fellowship.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Quantification of PC12 cell survival using Trypan Blue assay. (PDF 234 kb)
Quantification of neurite outgrowth following syntaxin1 knockdown. (PDF 290 kb)
Neuronal growth cones show syntaxin3 immunoreactivity. (PDF 1269 kb)
Increase in alpha-helical content of syntaxin3 and SNAP-25 upon their interaction. (PDF 371 kb)
Structure of fatty acids used in the syntaxin3 screen. (PDF 161 kb)
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Darios, F., Davletov, B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440, 813–817 (2006). https://doi.org/10.1038/nature04598
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