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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Futerman, A. H. & Banker, G. A. The economics of neurite outgrowth: the addition of new membrane to growing axons. Trends Neurosci. 19, 144–149 (1996)
Negre-Aminou, P., Nemenoff, R. A., Wood, M. R., de la Houssaye, B. A. & Pfenninger, K. H. Characterization of phospholipase A2 activity enriched in the nerve growth cone. J. Neurochem. 67, 2599–2608 (1996)
Hornfelt, M., Ekstrom, P. A. & Edstrom, A. Involvement of axonal phospholipase A2 activity in the outgrowth of adult mouse sensory axons in vitro. Neuroscience 91, 1539–1547 (1999)
Kelly, R. B. Deconstructing membrane traffic. Trends Cell Biol. 9, M29–M33 (1999)
Sofroniew, M. V., Howe, C. L. & Mobley, W. C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281 (2001)
Greene, L. A. & Tischler, A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl Acad. Sci. USA 73, 2424–2428 (1976)
Zheng, W. H., Fink, D. W. Jr & Guroff, G. Role of protein kinase C α in nerve growth factor-induced arachidonic acid release from PC12 cells. J. Neurochem. 66, 1868–1875 (1996)
Rizo, J. & Sudhof, T. C. SNAREs and Munc18 in synaptic vesicle fusion. Nature Rev. Neurosci. 3, 641–653 (2002)
Ungar, D. & Hughson, F. M. SNARE protein structure and function. Annu. Rev. Cell Dev. Biol. 19, 493–517 (2003)
Wenk, M. R. & De Camilli, P. Protein–lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals. Proc. Natl Acad. Sci. USA 101, 8262–8269 (2004)
Rohrbough, J. & Broadie, K. Lipid regulation of the synaptic vesicle cycle. Nature Rev. Neurosci. 6, 139–150 (2005)
Rickman, C. & Davletov, B. Arachidonic acid allows SNARE complex formation in the presence of Munc18. Chem. Biol. 12, 545–553 (2005)
Tang, B. L. Protein trafficking mechanisms associated with neurite outgrowth and polarized sorting in neurons. J. Neurochem. 79, 923–930 (2001)
Bajohrs, M., Darios, F., Peak-Chew, S. Y. & Davletov, B. Promiscuous interaction of SNAP-25 with all plasma membrane syntaxins in a neuroendocrine cell. Biochem. J. 392, 283–289 (2005)
Schiavo, G., Shone, C. C., Bennett, M. K., Scheller, R. H. & Montecucco, C. Botulinum neurotoxin type C cleaves a single Lys–Ala bond within the carboxyl-terminal region of syntaxins. J. Biol. Chem. 270, 10566–10570 (1995)
Igarashi, M. et al. Growth cone collapse and inhibition of neurite growth by Botulinum neurotoxin C1: a t-SNARE is involved in axonal growth. J. Cell Biol. 134, 205–215 (1996)
Osen-Sand, A. et al. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature 364, 445–448 (1993)
Farkas, T. et al. Docosahexaenoic acid-containing phospholipid molecular species in brains of vertebrates. Proc. Natl Acad. Sci. USA 97, 6362–6366 (2000)
Wainwright, P. E. Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc. Nutr. Soc. 61, 61–69 (2002)
Brash, A. R. Arachidonic acid as a bioactive molecule. J. Clin. Invest. 107, 1339–1345 (2001)
Negre-Aminou, P. & Pfenninger, K. H. Arachidonic acid turnover and phospholipase A2 activity in neuronal growth cones. J. Neurochem. 60, 1126–1136 (1993)
Fasshauer, D., Bruns, D., Shen, B., Jahn, R. & Brunger, A. T. A structural change occurs upon binding of syntaxin to SNAP-25. J. Biol. Chem. 272, 4582–4590 (1997)
Lakowicz, J. R. Principles of Fluorescence Spectroscopy (Kluwer Academic/Plenum, New York, 1999)
Kane, C. D. & Bernlohr, D. A. A simple assay for intracellular lipid-binding proteins using displacement of 1-anilinonaphthalene 8-sulfonic acid. Anal. Biochem. 233, 197–204 (1996)
Fasshauer, D., Antonin, W., Margittai, M., Pabst, S. & Jahn, R. Mixed and non-cognate SNARE complexes. Characterization of assembly and biophysical properties. J. Biol. Chem. 274, 15440–15446 (1999)
Galli, T. et al. A novel tetanus neurotoxin-insensitive vesicle-associated membrane protein in SNARE complexes of the apical plasma membrane of epithelial cells. Mol. Biol. Cell 9, 1437–1448 (1998)
Marszalek, J. R. & Lodish, H. F. Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you. Annu. Rev. Cell Dev. Biol. 21, 633–657 (2005)
Hamilton, J. A. Fatty acid interactions with proteins: what X-ray crystal and NMR solution structures tell us. Prog. Lipid Res. 43, 177–199 (2004)
Nakamura, S. Involvement of phospholipase A2 in axonal regeneration of brain noradrenergic neurones. Neuroreport 4, 371–374 (1993)
Bading, H. & Greenberg, M. E. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912–914 (1991)
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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