Professor Frederic Meunier obtained his Masters degree in Neurophysiology at the Paris XI University, France in 1992 and completed his Ph.D in Neurobiology at the CNRS in Gif-sur-Yvette, France in 1996. He was the recipient of a European Biotechnology Fellowship and went on to postgraduate work at the Department of Biochemistry at Imperial College (1997-1999) and at Cancer Research UK (2000-2002) in London, UK. After a short sabbatical at the LMB-MRC in Cambridge (UK), he became a group leader at the School of Biomedical Sciences at the University of Queensland (Australia) in 2003. He joined the Queensland Brain Institute of the University of Queensland in 2007 and obtained an NHMRC senior research fellowship in 2009 renewed in 2014 with promotion. In 2014 he was also promoted to Professor and joined the Centre for Ageing Dementia Research headed by Prof Juergen Goetz at QBI.
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).
- Dr Brett Collins - Institute for Molecular Bioscience, The University of Queensland
- Dr Thomas Fath - Faculty of Medicine, University of New South Wales
- Professor Phil Robinson - Children’s Medical Research Institute (CMRI)
- Associate Professor Elizabeth Coulsen - Queensland Brain Institute, The University of Queensland
- Associate Professor Peter Noakes - School of Biomedical Sciences, The University of Queensland
- Dr Nickolas Lavidis - School of Biomedical Sciences, The University of Queensland
- Dr Shanker Karunanithi - Queensland Brain Institute, The University of Queensland
- Associate Professor Bruno van Swinderen - Queensland Brain Institute, The University of Queensland
- Dr Marc Ruitenberg - School of Biomedical Sciences, The University of Queensland
- Dr Thiruma (Garrie) Arumugam - School of Biomedical Sciences, The University of Queensland
- Associate Professor Stephen Mahler - Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
- Professor Adam McCluskey - Chemistry, School of Environmental and Life Sciences, University of Newcastle
- Professor Jenny Stow - Institute for Molecular Bioscience, The University of Queensland
- Professor Robert Parton - Institute for Molecular Bioscience, The University of Queensland
- Associate Professor Damien Keating - School of Medicine, Flinders University
- 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, Canada
Narayana VK, Tomatis VM, Wang T, Kvaskoff D, Meunier FA.(2015) Profiling of Free Fatty Acids Using Stable Isotope Tagging Uncovers a Role for Saturated Fatty Acids in Neuroexocytosis. Chem Biol. 22: 1552-1561
Jackson J, Papadopulos A, Meunier FA, McCluskey A, Robinson PJ, Keating DJ. (2015) Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release. Mol Psychiatry. 20: 810-9
Wang T, Martin S, Papadopulos A, Harper CB, Mavlyutov TA, Niranjan D, Glass NR, Cooper-White JJ, Sibarita JB, Choquet D, Davletov B, Meunier FA. (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a. J Neurosci. 35:6179-94.
Gormal RS, Nguyen TH, Martin S, Papadopulos A, Meunier FA (2015) An acto-myosin-II constricting ring initiates the fission of activity-dependent bulk endosomes in neurosecretory cells. Journal of Neuroscience. 35: 1380-1389.
Papadopulos A, Gomez G, Martin S, Jackson J, Gormal RS, Keating DJ, Yap A Meunier FA (2015). Activity-driven relaxation of the cortical acto-myosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking. Nature Communications. 6:6297.
Low PC, Manzanero S, Mohannak N, Narayana VK, Nguyen TH, Kvaskoff D, Brennan FH, Ruitenberg MJ, Gelderblom M, Magnus T, Kim HA, Broughton BRS, Sobey CG, Vanhaesebroeck B, Stow JL, Arumugam TV, Meunier FA (2014) PI 3-kinase d inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nature Communications. 5:3450
Martin S, Papadopulos A, Tomatis VM, Sierecki E, Malintan NT, Gormal RS, Giles N, Johnston WA, Alexandrov K, Gambin Y, Collins BM, Meunier FA. (2014) Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis. Cell Reports. 9:206-18
Martin S, Harper CB, May LM, Coulson EJ, Meunier FA, Osborne SL (2013) Inhibition of PIKfyve by YM-201636 dysregulates autophagy and leads to apoptosis-independent neuronal cell death. PLoS One, 8: e60152.
McCluskey A, Daniel JA, Hadzic G, Chau N, Clayton EL, Mariana A, Whiting A, Gorgani NN, Lloyd J, Quan A, Moshkanbaryans L, Krishnan S, Perera S, Chircop M, von Kleist L, McGeachie AB, Howes MT, Parton RG, Campbell M, Sakoff JA, Wang X, Sun JY, Robertson MJ, Deane FM, Nguyen TH, Meunier FA, Cousin MA, Robinson PJ (2013) Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis. Traffic, 14: 1272-89.
Papadopulos A., Martin S., Tomatis VM, Gormal R., Meunier, F. A. (2013). Secretagogue stimulation of neurosecretory cells elicits filopodial extensions uncovering new functional release sites. J. Neurosci. 33(49):19143-53.
Tomatis VM, Papadopulos A, Malintan NT, Martin S, Wallis T, Gormal RS, Kendrick Jones J, Buss F and Meunier, F. A. (2013). Myosin VI small insert isoform maintains neuroexocytosis by tethering secretory granule to the cortical actin network. Journal of Cell Biology., 200(3):301-20.
Martin S, Tomatis VM, Papadopulos A, Christie MP, Malintan NT, Gormal RS, Sugita S, Martin JL, Collins BM, Meunier, F. A. (2013). The Munc18-1 domain 3a loop is essential for neuroexocytosis but not for syntaxin-1A transport to the plasma membrane. J. Cell Sci., 126:2353-60.
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 23(2):90-101.
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.
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.
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.
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.
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.
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.
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.
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., 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.