Associate Professor Frederic Meunier - Neuronal trafficking

Research directions

Neurons can reach astonishing shapes and dimensions (several metres can separate the dendrites from the nerve terminal in certain species). How these highly polarized cells can maintain their function throughout life is one of the key questions that interest our lab. The maintenance of this polarity is achieved through the traffic and transport of membrane compartments called vesicles. These vesicles, which have various origins and defined destinations, underpin fundamental functions such as neuronal communication through the timely release of neurotransmitter at the synapse. They can also be destined for retrograde transport, carrying many important survival factors from the synapse back to the cell body.

We are using new fluorescent probes and state-of-the-art live cell microscopy, in combination with the power of proteomics, electrophysiology, structural biology and biochemistry, to understand the molecular mechanisms underpinning some of the many different forms of neuronal membrane trafficking.

Our knowledge regarding neuronal biology is currently being enlightened by advances in membrane trafficking whether it is an ion channel regulated through an endosomal cycle or through the discovery of a novel trafficking pathway in neurons important for survival. Novel pharmacology based on membrane trafficking is emerging and could provide answers to previously intractable problems involving the aged or diseased nervous system.

The focus of our laboratory is to decipher the dynamics of molecular events taking place during exo- and endocytosis in neurons and neurosecretory cells. Our ultimate aim is to understand the sequence of molecular interactions underpinning processes such as the release of neurotransmitter, the recycling of synaptic vesicles, and the internalisation and trafficking of extracellular survival factors. 

Current collaborations

Selected publications

Kerr MC, Wang JT, Castro NA, Hamilton NA, Town L, Brown DL, Meunier FA, Brown NF, Stow JL, Teasdale RD. (2010) Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella. EMBO J. 2010 Mar 18. [Epub ahead of print]

Meunier, F.A. Nguyen T.H., Colasante C., Luo F., Sullivan RKP, Lavidis NA.,  MolgóJ., Meriney SD., and Schiavo G. (2010). Sustained synaptic vesicle recycling by bulk endocytosis contributes to maintaining high-rate neurotransmitter release stimulated by Glycerotoxin J. Cell Sci. 123:1131-40

Han L, Jiang T, Han GA, Malintan NT, Xie L, Wang L, Tse FW, Gaisano HY, Collins BM, Meunier FA, 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. 23:4962-4975.

Nguyen-Huu TD, Mattei C, Wen PJ, Bourdelais AJ, Lewis RJ, Benoit E, Baden DG, Molgó J, Meunier FA. (2009) Ciguatoxin-induced catecholamine secretion in bovine chromaffin cells: Mechanism of action and reversible inhibition by brevenal. Toxicon. Epub ahead of print.

Malintan NT, Nguyen TH, Han L, Latham CF, Osborne SL, Wen PJ, Lim SJ, Sugita S, Collins BM, Meunier FA. (2009) Abrogating Munc18-1-SNARE complex interaction has limited impact on exocytosis in PC12 Cells. J Biol Chem 32:21637-46

Meunier FA, Mattei C, Molgo J. (2009) Marine toxins affecting neurotransmitter release. J Biol Chem, 46:159-86

Mattei C, Wen PJ, Nguyen-Huu TD, Alvarez M, Benoit E, Bourdelais AJ, Lewis RJ, Baden DG, Molgó J, Meunier FA. (2009) Brevenal inhibits pacific ciguatoxin-1B-induced neurosecretion from bovine chromaffin cells. PLoS One, 3:e3448

Wen PJ, Osborne SL, Morrow IC, Parton RG, Domin J, Meunier FA (2008) Ca2+-regulated pool of phosphatidylinositol-3-phosphate produced by phosphatidylinositol 3-kinase C2alpha on neurosecretory vesicles. Mol Biol Cell, 12:5593-603

Coulson EJ, May LM, Osborne SL, Reid K, Underwood CK, Meunier FA, Bartlett PF, Sah P (2008) p75 neurotrophin receptor mediates neuronal cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate. J Neurosci. 2,28:315-24

Osborne S.L., Wen P.J., Boucheron C., Nguyen H.N., Hayakawa M., Kaizawa H., Parker P.J., Vitale N., and Meunier F.A. (2008). PIKfyve negatively regulates exocytosis in neurosecretory cells. J. Biol. Chem Epub ahead of print.

Osborne S.L., Wallis T.P., Jimenez J.L., Gorman J.J. and Meunier F.A. (2007). Identification of secretory granule phosphatidylinositol 4,5-bisphosphate-interacting proteins using an affinity pulldown strategy. Mol. Cell Proteomics 6:1158-1169.

Latham C.F., Osborne S.L., Cryle M.J., and Meunier F.A. (2006). Arachidonic acid potentiates exocytosis and allows neuronal SNARE complex to interact with Munc18a. J Neurochem. 100:1543-54.

Schenning M, Proctor DT, Ragnarsson L, Barbier J, Lavidis NA, Molgo J, Zamponi GW, Schiavo G, and Meunier, F.A. (2006). Glycerotoxin stimulates neurotransmitter release from N-type Ca2+ channel expressing neurons.J Neurochem. 98:894-904.

Rickman C., Meunier F.A., Binz T. and Davletov B.A. (2004). High affinity interaction of syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E. J. Biol. Chem. 279: 644-651.

Meunier F.A., Osborne S.L., Hammond G., Cooke F.T., Parker P.J., Domin J. and Schiavo G. (2005). PI3-kinase C2 is essential for ATP-dependent priming of neurosecretory granule exocytosis. Mol Biol Cell. 16:4841-51.

Meunier F.A., Lisk G., Sesardic D. and Dolly J.O. (2003). Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins. Molecular Cellular Neuroscience 22: 454-466.

Meunier F.A., Feng Z.P., Molgo J., Zamponi G. and Schiavo G. (2002). Glycerotoxin from Glycera convoluta stimulates neurosecretion by targeting N-type Ca2+ channels Cav2.2. EMBO J. 21: 6733-6743.

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

De Paiva A., Meunier F.A., Molgo J., Aoki R. and Dolly J.O., (1999). Basis of the functional repair of paralysed motor nerve endings: A bi-phasic switch in the loci of synaptic activity between nerve terminals and their botulinum toxin A-induced sprouts. Proc. Natl. Acad. Sci. U.S.A. 96: 3200-3205.

Davletov B.A., Meunier F.A., Ashton A.C., Matsushita H., Hirst W.D., Lelianova V.G., Wilkin G.P., Dolly J.O., and Ushkaryov Y.A. (1998). Vesicle exocytosis stimulated by alpha-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+. EMBO J. 17: 3909-3920.

Reviews 

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

Meunier F.A., Schiavo G., and Molgo, J. (2002). Botulinum neurotoxins: from paralysis to recovery of functional neuromuscular transmission. J. Physiol. (Paris) 96:105-113.

Foran P.G., Davletov B., and Meunier F.A. (2003). Getting muscles moving again after botulinum toxin: novel therapeutic challenges. Trends in Molecular Medicine 9: 9291-299.

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

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

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