Associate Professor Frederic Meunier - Neuronal trafficking

Research directions

The overall goal of our research is to determine how brain cells communicate and survive in health and disease. Our lab focuses on the molecular events governing vesicular trafficking within presynaptic nerve terminals and neurosecretory cells. Our discoveries have led to a deep understanding of how secretory vesicles interact with the cortical actin network on their way to fuse with the plasma membrane to release the neurotransmitter. We have identified a critical role played by the phospholipid phosphatidylinositol (4,5) bisphosphate in coordinating an actin-mediated recruitment of secretory vesicles to the plasma membrane. This active mechanism allows secretory mechanism to dock with the plasma membrane prior fusion and is controlled by the effector cdc42. This discovery published in the journal Nature Communications was highlighted as a must read in the F1000. We have recently uncovered a new mechanism allowing secretory vesicles to be recruited on the cortical actin network. In a stream of publications, we demonstrated that the protein Munc18-1 was responsible for the transport of Syntaxin-1 to the plasma membrane. This novel trafficking/chaperoning pathway underpins neurotransmission as secretory vesicles rely on the zippering of SNARE proteins such as Syntaxin-1 to undergo fusion with the plasma membrane. The flip side of exocytosis is endocytosis, a process by which neurons replenish their pools of synaptic vesicles by pinching off vesicles from the plasma membrane. We have identified a completely novel mechanism by which dynamin and actin coordinate a series of membrane events culminating in the formation of bulk endosomes from which new synaptic vesicles emanates at the neuromuscular junction. We have also demonstrated that dynamin is a valid prophylactic target against infection and intoxication. We provided a proof of concept that dynamin inhibitors such as Dyngo4a were effective in blocking the internalisation of the deadly botulinum neurotoxin in nerve terminals. This study was published in the Journal of Biological Chemistry and was flagged by the F1000 and SciBX. As a result, we received an invitation to review the field of dynamin inhibitors as potential prophylactic treatment again infection in the famous Trends in Cell Biology.
Our lab is keen on taking on highly motivated and high achieving students (Honours and PhD).

Current collaborations

Australia

• Dr. Brett Collins, Institute for Molecular Bioscience, The University of Queensland, St Lucia QLD 4072, Australia
• Dr. Thomas Fath, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
• Professor Phil Robinson (CMRI), Children’s Medical Research Institute, Westmead, NSW, 2145, Australia
• Associate Professor Elizabeth Coulsen, Queensland Brain Institute, The University of Queensland, St Lucia QLD 4072, Australia
• Associate Professor Peter Noakes, School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia
• Dr Nickolas Lavidis, School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia
• Dr. Shanker Karunanithi, Queensland Brain Institute, The University of Queensland, St Lucia QLD 4072, Australia
• Associate Professor Bruno van Swinderen, Queensland Brain Institute, The University of Queensland, St Lucia QLD 4072, Australia
• Dr Marc Ruitenberg, School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia
• Dr Thiruma (Garrie) Arumugam, School of Biomedical Sciences, The University of Queensland, St Lucia QLD 4072, Australia
• Associate Professor Stephen Mahler, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia QLD 4072, Australia
• Professor Adam McCluskey, Chemistry, School of Environmental and Life Sciences, University of Newcastle, Callaghan, New South Wales 2308, Australia
• Professor Jenny Stow, Institute for Molecular Bioscience, The University of Queensland, St Lucia QLD 4072, Australia
• Professor Robert Parton, Institute for Molecular Bioscience, The University of Queensland, St Lucia QLD 4072, Australia
• Associate Professor Damien Keating, School of Medicine, Flinders University, Adelaide SA, 5001, Australia

International

•  Dr. Daniel Choquet, Dynamics of Synapse Organisation and Function Laboratory, Interdisciplinary Institute for Neuroscience, Bordeaux, France
•  Dr. Michel R Popoff, Unit for Anaerobic Bacteria and Toxins, Institute Pasteur, Paris, France
•  Professor Jianyuan Sun, The Institute of Biophysics, The Chinese Academy of Science, Beijing, China.
•  Dr. Shuzo Sugita, Division of Fundamental Neurobiology
• Toronto Western Research Institute, Toronto, Ontario, Canada

Selected publications

Harper, C. B., Popoff, M. R., McCluskey, A., Robinson, P. J., and Meunier, F. A. 2012 Targeting membrane trafficking in infection prophylaxis: dynamin inhibitors. Trends Cell Biol Nov 16. [Epub ahead of print]

Wen, P. J., Osborne, S. L. & Meunier, F. A. 2012. Phosphoinositides in neuroexocytosis and neuronal diseases. Curr Top Microbiol Immunol, 362, 87-98.

Nguyen, T. H., Maucort, G., Sullivan, R. K., Schenning, M., Lavidis, N. A., McCluskey, A., Robinson, P. J. & Meunier, F. A. 2012. Actin- and dynamin-dependent maturation of bulk endocytosis restores neurotransmission following synaptic depletion. PLoS One, 7, e36913.

Wen, P. J., Osborne, S. L., Zanin, M., Low, P. C., Wang, H. T., Schoenwaelder, S. M., Jackson, S. P., Wedlich-Soldner, R., Vanhaesebroeck, B., Keating, D. J. & Meunier, F. A. 2011a. Phosphatidylinositol(4,5)bisphosphate coordinates actin-mediated mobilization and translocation of secretory vesicles to the plasma membrane of chromaffin cells. Nat Commun, 2, 491.

Wen, P. J., Osborne, S. L. & Meunier, F. A. 2011b. Dynamic control of neuroexocytosis by phosphoinositides in health and disease. Prog Lipid Res, 50, 52-61.

Harper, C. B., Martin, S., Nguyen, T. H., Daniels, S. J., Lavidis, N. A., Popoff, M. R., Hadzic, G., Mariana, A., Chau, N., McCluskey, A., Robinson, P. J. & Meunier, F. A. 2011. Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism. J Biol Chem, 286, 35966-76.

Han, G. A., Malintan, N. T., Saw, N. M., Li, L., Han, L., Meunier, F. A., Collins, B. M. & Sugita, S. 2011. Munc18-1 domain-1 controls vesicle docking and secretion by interacting with syntaxin-1 and chaperoning it to the plasma membrane. Mol Biol Cell, 22, 4134-49.

Nguyen-Huu, T. D., Mattei, C., Wen, P. J., Bourdelais, A. J., Lewis, R. J., Benoit, E., Baden, D. G., Molgo, J. & Meunier, F. A. 2010. Ciguatoxin-induced catecholamine secretion in bovine chromaffin cells: mechanism of action and reversible inhibition by brevenal. Toxicon, 56, 792-6.

Meunier, F. A., Nguyen, T. H., Colasante, C., Luo, F., Sullivan, R. K., Lavidis, N. A., Molgo, J., Meriney, S. D. & Schiavo, G. 2010. Sustained synaptic-vesicle recycling by bulk endocytosis contributes to the maintenance of high-rate neurotransmitter release stimulated by glycerotoxin. J Cell Sci, 123, 1131-40.

Low, P. C., Misaki, R., Schroder, K., Stanley, A. C., Sweet, M. J., Teasdale, R. D., Vanhaesebroeck, B., Meunier, F. A., Taguchi, T. & Stow, J. L. 2010. Phosphoinositide 3-kinase delta regulates membrane fission of Golgi carriers for selective cytokine secretion. J Cell Biol, 190, 1053-65.

Kerr, M. C., Wang, J. T., Castro, N. A., Hamilton, N. A., Town, L., Brown, D. L., Meunier, F. A., Brown, N. F., Stow, J. L. & Teasdale, R. D. 2010. Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella. EMBO J, 29, 1331-47.

Han, G. A., Malintan, N. T., Collins, B. M., Meunier, F. A. & Sugita, S. 2010. Munc18-1 as a key regulator of neurosecretion. J Neurochem, 115, 1-10.

Chasserot-Golaz, S., Coorssen, J. R., Meunier, F. A. & Vitale, N. 2010. Lipid dynamics in exocytosis. Cell Mol Neurobiol, 30, 1335-42.

Anderson, R. J., Osborne, S. L., Meunier, F. A. & Painter, G. F. 2010. Regioselective approach to phosphatidylinositol 3,5-bisphosphates: syntheses of the native phospholipid and biotinylated short-chain derivative. J Org Chem, 75, 3541-51.

Meunier, F. A., Mattei, C. & Molgo, J. 2009. Marine toxins potently affecting neurotransmitter release. Prog Mol Subcell Biol, 46, 159-86.

Malintan, N. T., Nguyen, T. H., Han, L., Latham, C. F., Osborne, S. L., Wen, P. J., Lim, S. J., Sugita, S., Collins, B. M. & Meunier, F. A. 2009. Abrogating Munc18-1-SNARE complex interaction has limited impact on exocytosis in PC12 cells. J Biol Chem, 284, 21637-46.

Han, L., Jiang, T., Han, G. A., Malintan, N. T., Xie, L., Wang, L., Tse, F. W., Gaisano, H. Y., Collins, B. M., Meunier, F. A. & Sugita, S. 2009. Rescue of Munc18-1 and -2 double knockdown reveals the essential functions of interaction between Munc18 and closed syntaxin in PC12 cells. Mol Biol Cell, 20, 4962-75.

Wen, P. J., Osborne, S. L., Morrow, I. C., Parton, R. G., Domin, J. & Meunier, F. A. 2008. Ca2+-regulated pool of phosphatidylinositol-3-phosphate produced by phosphatidylinositol 3-kinase C2alpha on neurosecretory vesicles. Mol Biol Cell, 19, 5593-603.

Osborne, S. L., Wen, P. J., Boucheron, C., Nguyen, H. N., Hayakawa, M., Kaizawa, H., Parker, P. J., Vitale, N. & Meunier, F. A. 2008. PIKfyve negatively regulates exocytosis in neurosecretory cells. J Biol Chem, 283, 2804-13.

Mattei, C., Wen, P. J., Nguyen-Huu, T. D., Alvarez, M., Benoit, E., Bourdelais, A. J., Lewis, R. J., Baden, D. G., Molgo, J. & Meunier, F. A. 2008. Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells. PLoS One, 3, e3448.

Coulson, E. J., May, L. M., Osborne, S. L., Reid, K., Underwood, C. K., Meunier, F. A., Bartlett, P. F. & Sah, P. 2008. p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. J Neurosci, 28, 315-24.

Osborne, S. L., Wallis, T. P., Jimenez, J. L., Gorman, J. J. & Meunier, F. A. 2007a. Identification of secretory granule phosphatidylinositol 4,5-bisphosphate-interacting proteins using an affinity pulldown strategy. Mol Cell Proteomics, 6, 1158-69.

Osborne, S. L., Latham, C. F., Wen, P. J., Cavaignac, S., Fanning, J., Foran, P. G. & Meunier, F. A. 2007b. The Janus faces of botulinum neurotoxin: sensational medicine and deadly biological weapon. J Neurosci Res, 85, 1149-58.

Latham, C. F., Osborne, S. L., Cryle, M. J. & Meunier, F. A. 2007. Arachidonic acid potentiates exocytosis and allows neuronal SNARE complex to interact with Munc18a. J Neurochem, 100, 1543-54.

Latham, C. F. & Meunier, F. A. 2007. Munc18a: Munc-y business in mediating exocytosis. Int J Biochem Cell Biol, 39, 1576-81.

Sim, A. T., Herd, L., Proctor, D. T., Baldwin, M. L., Meunier, F. A. & Rostas, J. A. 2006. High throughput analysis of endogenous glutamate release using a fluorescence plate reader. J Neurosci Methods, 153, 43-7.

Schenning, M., Proctor, D. T., Ragnarsson, L., Barbier, J., Lavidis, N. A., Molgo, J. J., Zamponi, G. W., Schiavo, G. & Meunier, F. A. 2006. Glycerotoxin stimulates neurotransmitter release from N-type Ca2+ channel expressing neurons. J Neurochem, 98, 894-904.

Osborne, S. L., Wen, P. J. & Meunier, F. A. 2006. Phosphoinositide regulation of neuroexocytosis: adding to the complexity. J Neurochem, 98, 336-42.

Meunier, F. A., Osborne, S. L., Hammond, G. R., Cooke, F. T., Parker, P. J., Domin, J. & Schiavo, G. 2005. Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol Biol Cell, 16, 4841-51.

Clark, R. J., Fischer, H., Dempster, L., Daly, N. L., Rosengren, K. J., Nevin, S. T., Meunier, F. A., Adams, D. J. & Craik, D. J. 2005. Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII. Proc Natl Acad Sci U S A, 102, 13767-72.

Rickman, C., Meunier, F. A., Binz, T. & Davletov, B. 2004a. High affinity interaction of syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E. J Biol Chem, 279, 644-51.

Rickman, C., Archer, D. A., Meunier, F. A., Craxton, M., Fukuda, M., Burgoyne, R. D. & Davletov, B. 2004b. Synaptotagmin interaction with the syntaxin/SNAP-25 dimer is mediated by an evolutionarily conserved motif and is sensitive to inositol hexakisphosphate. J Biol Chem, 279, 12574-9.

Meunier, F. A., Lisk, G., Sesardic, D. & Dolly, J. O. 2003. Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation. Mol Cell Neurosci, 22, 454-66.

Jimenez, J. L., Smith, G. R., Contreras-Moreira, B., Sgouros, J. G., Meunier, F. A., Bates, P. A. & Schiavo, G. 2003. Functional recycling of C2 domains throughout evolution: a comparative study of synaptotagmin, protein kinase C and phospholipase C by sequence, structural and modelling approaches. J Mol Biol,
333, 621-39.

Foran, P. G., Davletov, B. & Meunier, F. A. 2003. Getting muscles moving again after botulinum toxin: novel therapeutic challenges. Trends Mol Med, 9, 291-9.

Meunier, F. A., Schiavo, G. & Molgo, J. 2002a. Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. J Physiol Paris, 96, 105-13.

Meunier, F. A., Feng, Z. P., Molgo, J., Zamponi, G. W. & Schiavo, G. 2002b. Glycerotoxin from Glycera convoluta stimulates neurosecretion by up-regulating N-type Ca2+ channel activity. EMBO J, 21, 6733-43.

Benoit, E., Mattei, C., Ouanounou, G., Meunier, F. A., Suput, D., Le Gall, F., Marquais, M., Dechraoui, M. Y. & Molgo, J. 2002. Ionic mechanisms involved in the nodal swelling of myelinated axons caused by marine toxins. Cell Mol Biol Lett, 7, 317-21.

Osborne, S. L., Meunier, F. A. & Schiavo, G. 2001. Phosphoinositides as key regulators of synaptic function. Neuron, 32, 9-12.

Volynski, K. E., Meunier, F. A., Lelianova, V. G., Dudina, E. E., Volkova, T. M., Rahman, M. A., Manser, C., Grishin, E. V., Dolly, J. O., Ashley, R. H. & Ushkaryov, Y. A. 2000. Latrophilin, neurexin, and their signaling-deficient mutants facilitate alpha -latrotoxin insertion into membranes but are not involved in pore
formation. J Biol Chem, 275, 41175-83.

Sauviat, M. P., Meunier, F. A., Kreger, A. & Molgo, J. 2000. Effects of trachynilysin, a protein isolated from stonefish (Synanceia trachynis) venom, on frog atrial heart muscle. Toxicon, 38, 945-59.

Meunier, F. A., Mattei, C., Chameau, P., Lawrence, G., Colasante, C., Kreger, A. S., Dolly, J. O. & Molgo, J. 2000a. Trachynilysin mediates SNARE-dependent release of catecholamines from chromaffin cells via external and stored Ca2+. J Cell Sci, 113 ( Pt 7), 1119-25.

Meunier, F. A., Frangez, R., Benoit, E., Ouanounou, G., Rouzaire-Dubois, B., Suput, D. & Molgo, J. 2000b. Ca(2+) and Na(+) contribute to the swelling of differentiated neuroblastoma cells induced by equinatoxin-II. Toxicon, 38, 1547-60.

Shamotienko, O., Akhtar, S., Sidera, C., Meunier, F. A., Ink, B., Weir, M. & Dolly, J. O. 1999. Recreation of neuronal Kv1 channel oligomers by expression in mammalian cells using Semliki Forest virus. Biochemistry, 38, 16766-76.

Rahman, M. A., Ashton, A. C., Meunier, F. A., Davletov, B. A., Dolly, J. O. & Ushkaryov, Y. A. 1999. Norepinephrine exocytosis stimulated by alpha-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Philos Trans R Soc Lond B Biol Sci, 354, 379-86.

Mattei, C., Dechraoui, M. Y., Molgo, J., Meunier, F. A., Legrand, A. M. & Benoit, E. 1999. Neurotoxins targetting receptor site 5 of voltage-dependent sodium channels increase the nodal volume of myelinated axons. J Neurosci Res, 55, 666-73.

de Paiva, A., Meunier, F. A., Molgo, J., Aoki, K. R. & Dolly, J. O. 1999. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A, 96, 3200-5.

Davletov, B. A., Meunier, F. A., Ashton, A. C., Matsushita, H., Hirst, W. D., Lelianova, V. G., Wilkin, G. P., Dolly, J. O. & Ushkaryov, Y. A. 1998. Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+. EMBO J, 17, 3909-20.

Lab Members


 

   

On this site