zhen
Mei ZhenPhD
Professor
Neuroscience Platform

Contact Info

T. (416) 586-1592
F. (416) 586-8588

Location

Rm. 870, Lunenfeld-Tanenbaum Research Institute, 600 University Ave, Mount Sinai Hospital
Toronto
ON, M5G 1X5

Research Interests

Optogenetics, genetics, molecular and cellular mechanisms that regulate the assembly and operation of motor circuit development and locomotion.

Accepting

None

Appointments

Primary: Molecular Genetics & Microbiology

Degrees: Ph.D. 1995

Affiliations: Lunenfeld-Tanenbaum Research Institute

Courses Taught: JYG155 (Current Topics in Molecular and Cellular Neurobiology); JDB1025H (Developmental Biology); MMG 1012H (Advanced Imaging: Techniques and Application in Biological Systems).

Research/Teaching

Research Synopsis:

Keywords:   calcium imaging, electrophysiology, motor behaviour, optogenetics, genetics, neural development

Detailed Description: We investigate how neural circuits enable motor behaviors. Using the C. elegans motor circuit as a model, we combine the classic genetics studies, optogenetics, electrophysiology and electron microscopy to answer the following questions: 1) How is the anatomic ensemble of the motor circuit regulated at the molecular and cellular level; 2) How does the C. elegans motor circuit generate rhythmic movement pattern; 3) Do any of the molecular determinants for cholinergic and GABAergic motor neuron development play conserved roles in other nervous systems?

C. elegans is an excellent experimental system for these studies: Its compact and fully sequenced genome, as well as the fast life cycle, allows for the application of powerful forward and reverse genetic tools; The connectivity of its simple nervous system has been deduced by EM reconstructions; the transparency of the animal, and the small number of neurons and synapses allow live imaging at single neuron and single synapse resolution; Physiology tools - in vivo calcium imaging and intracellular recording, are now available, expanding the horizon of functional analyses of nervous system development and function; Lastly, C. elegans exhibits a limited repertoire of motor behaviors that can be precisely quantified through automated tracking systems.

Approaches:
1. In collaboration with the Litchman and Samuel groups (Harvard University), we are using cutting-edge, automated EM technique to reconstruct the wiring of the C. elegans developing nervous system.

2. We developed an array of fluorescent markers that allow us to examine the axon and synapse morphology of C. elegans neurons. We perform genetic screens to identify C. elegans mutants that exhibit defective polarization and synapse morphology. Our subsequent molecular genetic characterization of these mutants leads to the identification of key regulators of neuronal development. 

3. We developed state-of-art movement tracking, electrophysiology, calcium imaging and optogenetics tools to interrogate the functional connectivity of the C. elegans neuromuscular system. Through these tools, we have demonstrated the presence of action potentials in C. elegans body wall muscles, and the role of a small group of premotor interneurons in controlling the directionality of C. elegans’ movement.

4. We are using the C. elegans GABAergic neurons and GABAergic NMJs to model human mental disorders.

METHODS USED

Cell and tissue culture: Neurons.

Procedures: Behavioural tests, electrophysiology, gene expression analysis, immunohistochemistry, immunocytochemistry, in-vitro electrophysiology, in-vivo electrophysiology, in-vivo calcium imaging, mass spectrometry, optogenetic manipulation, patch clamp, proteomics, qRT-PCR, RT-PCR, siRNA, voltage clamp, western blot

EQUIPMENT USED

Amplifier, analytical balances, benchtop centrifuge, blotting apparatus, calcium imaging system, confocoal microscope, culture hood, culture incubators, deconvolution fluorescence microscope, digitsl microscope, dissecting microscope, electrophysiology rig, EMCCD, fluorescence microscope, gel apparatus, HPLC, low- and high-speed centrifuge, mass spectrometer, micropipette puller, microwave oven, mini vortexer, stirrer/hot plate, stimulator, water baths.

PRESENT TRAINEES
Asuka (Sihui) Guan
Yangning Lu
Daniel  Witvliet
Shangbang Gao
Maria Lim (Ph.D)
Benjamin Mucalhy (Ph. D)
Yan Li (Ph. D)

PRESENT COLLABORATIONS

Within the Department of Physiology:
Shuzo Sugita

Outside the Department of Physiology:

James   Dennis                        Molecular Genetics/UT/Canada
Brent   Derry                          Molecular Genetics/UT/Canada
Peter    St George-Hyslop      CRND/UT/Canada
Andras  Nagy                         IMS/UT/Canada

Mark  Alkema                     Medical School, UMass/USA
John  Calarco                      Center for Systems Biology/Harvard /USA
Jeff   Litchman                  Center of Brain Science/Harvard/USA
Aravinthan   Samuel                      Physics/Harvard U/USA
Kang  Shen                          Biology/Stanford U/USA (HHMI)
Valerie Reinke                       Genetics/Yale U/USA
David  Miller                                    Cell and Developmental Biology/Vanderbilt/USA
Brock Grill                          University of Florida/Florida/USA

Xun  Huang                       Institute of Dev. Biol. and Genetics/CAS/China
Ralf  Schnabel                   Institut fuer Genetik/TU Braunschweig/Germany
Christian   Stigloher                   University of Wurzburg       
Jean-Louis  Besseasuea                Ecole Normale, INSERM/France

Publications and Awards

Recent Publications

2014

Hung, W. L., Wang, Y., Chitturi, J. and Zhen, M.* A C. elegans developmental decision requires insulin signaling-mediated neuron-intestine communication Development 141(8):1767-1779

2013

Hung, W. L., Hwang, C., Gao, S., Liao, E. H., Chitturi, J., Wang, Y., Li, H., Stigloher, C., Bessereau, J. L. and Zhen, M*. Attenuation of insulin signaling contributes to FSN-1-mediated regulation of synapse development (EMBO J., 32(12):1745-1760).

Xie, L., Gao, S., Alcaire, S.M., Wang, Y., Stagljar, I. and Zhen, M.* NLF-1 regulates neuronal excitability through a conserved sodium leak channel. Neuron 77(6): 1069-1082

Qi, Y., Po, M.D., Mac, P., Kawano, T., Jorgensen, E., Zhen, M. and Jin, Y. Dendritic hyperactivation of B-type motor neurons results in aberrant synchrony of the c. elegans motor circuit. Journal of Neuroscience 33(12): 5319-5325

2012

Wen, Q., Po, M.D., et al. Wyart, M., Chklovskii, D.B., Zhen, M. and Samuel, A.D.T. Proprioceptive coupling within motor neurons drives C. elegans forward locomotion. Neuron 76(4): 750-761.

Najarro, E.H., Wong, L., Zhen, M., Carpio, E.P., Goncharov, A., Garriga, G., Jin, Y. and Ackley, B. The C. elegans Flamingo Cadherin FMI-1 cell-non-autonomously regulates GABAergic synapse formation. Journal of Neuroscience 32(12): 4196-211.

Murakami T., Yang, S.P., Xie, L., Kawano, T. et al. Kaminski, C.F., Zhen, M. and St George-Hyslop, P.S. ALS mutations in FUS cause neuronal dysfunction and death by a dominant gain-of-function mechanism independent of TDP-43. Human Molecular Genetics 21(1): 1-9.

Po, M.D*, Calarco, J.A* and Zhen, M*. Releasing the inner inhibition of axon regeneration Neuron (in press)

2011

Kawano, T., Po, M.D., Gao, S., Leung, G., Ryu, W.S. and Zhen, M .* An imbalancing act: gap junctions reduce backward circuit activity to promote forward locomotion. Neuron 17 (4): 572-587.

Gao, S and Zhen, M.* Action potentials drive C. elegans body wall muscle contractions in Caenorhabditis elegans. Proceedings in the National Academy of Science USA 108(6): 2557-2562.

Murakami T., Yang, S.P., Xie, L., Kawano, T., Fu D., Mukai, A., Bohm, C., Chen, F., Robertson, J., Suzuki, H., Tartaglia, G.G., Vendruscolo, Kaminski Schierle G,S., Chan, F.T.S, Moloney, A., Crowther, D., Kaminski, C.F., Zhen, M ., St George-Hyslop, P.S. ALS mutations in FUS causes neuronal dysfunction and death in by a dominant gain-of-function mechanism independent of TDP-43. Human Molecular Genetics 2011 Oct 11. [Epub ahead of print].

Mok, C., Healey, M., Shekhara, T., Leroux, M. R., Heon, E.* and Zhen, M .* Mutations in a Soluble Guanylate Cyclase GCY-35 Modify Bardet-Biedl Syndrome-Associated Phenotypes. PLoS Genetics 7(10):e1002335.

Stigloher, C., Zhan, H., Zhen, M., Richmond, J., Bessereau, J.L. The presynaptic dense projection of the Caenorhabiditis elegans cholinergic neuromuscular junction localizes synaptic vesicles at the active zone through SYD-2/liprin and UNC-10/RIM-dependent interactions. Journal of Neuroscience 31(12): 4388-4396.

Bouhours, M., Po, M.D., Gao, S., Hung, W., Li, H., Georgiou, J., Roder, J.C. and Zhen, M.* A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel. Molecular Brain 4:16.

Sancar, F.**, Touroutine, D.**, Gao, S.**, Oh, H.J., Gendrel, M., Bessereau, J., Kim, H., Zhen, M . and Richmond, J.E. The dystrophin-associated protein complex maintains muscle excitability by regulating BK channel localization. (**equal contribution) Journal of Biological Chemistry 286: 33501-33510.

Calarco, J., Zhen M. , and Blencowe, B.J. Networking in a global world: establishing functional connections between splicing regulators and their target transcripts. RNA . 17(5):775-91.

Ramani, A.K. ** , Calarco, J.A. . ** , Pan, Q., Mavandadi, S., Wang, Y., Nelson A.C., Lee, L.J., Morris, Q., B.J. Blencowe, Zhen, M . * and Fraser, A.G. * Genome-wide analysis of alternative splicing in Caenorhabditis elegans . Genome Research 21: 342-348 (**equal contributions).

2010

Souza R.P., Rosa D.V., Romano-Silva M.A., Zhen, M. , Meltzer H.Y., Lieberman J.A., Remington G., Kennedy J.L., Wong A.H. Lack of association of NALCN genetic variants with schizophrenia. Psychiatry Res . 185(3): 450-452.

Po, M., Hwang, C. and Zhen, M.* PHRs: bridging axon guidance, outgrowth and synapse development. Current Opinion in Neurobiology 20(1): 100-107.

Kim, J.S.M., Hung, W. and Zhen, M .* The Long and the Short of SAD-1 Kinase. Communicative and Integrative Biology 3(3): 1-5.

Kim, J.S.M., Hung, W., Narbonne, P., Roy, R., and Zhen, M .* C. elegans STRADα and SAD Cooperatively Regulate Neuronal Polarity and Synaptic Organization. Development 137(1): 93-102.

Mok, C., Heon, E. and Zhen, M.* Ciliary dysfunction and obesity. Clinical Genetics 77(1): 18-27.

2009

Calarco, J.A., Superina, S., O’Hanlon, D., Gabut, M., Raj, B., Pan, Q., Skalska, U., Clarke, L., Gelinas, van der Kooy, D., Zhen, M. , Ciruna, B., and Blencowe, B.G. Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein. Cell 138: 1-13.

Yeh, E., Kawano, T., Ng, S., Hung, W., Wang, Y., and Zhen, M.* C. elegans Innexins Regulate Active Zone Differentiation. Journal of Neuroscience 29(16): 5207-17.

2008

Liewald, J.F., Brauner, M., Stephens, G.J., Bouhours, M., Schultheis C., and Zhen, M. , Gottschalk, A. Optogenetic analysis of synaptic function. Nature Methods 5(10): 895-902.

Kim, J.S.M., Lilley, B.N., Zhang, C., Shokat, K.M., Sanes, J.R., and Zhen, M.* A chemical-genetic strategy reveals distinct temporal requirements for SAD-1 kinase in neuronal polarization and synapse formation. Neural Development 3(1): 23.

Li, C., Inglis, P.N., Leitch, C.C., Efimenko, E., Zaghoul, N.A., Mok, C.A., Davis, E.E., Bialas, N., Healey, M.P., Heon, E., Zhen, M ., Swoboda, P., Katsanis, N. and Leroux, M.R. An Essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes. PLoS Genetics 4(3): e1000044.

Yeh, E., Ng, S., Zhang, M., Bouhours, M., Wang, M., Wang, Y., Hung, W., Aoyagi, K., Melnik-Martinez, K., Li, M., Liu, F., Schafer, W., and Zhen, M.* A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans. PLoS Biology 6(3) e55.

Gao, M.X., Liao, E., Yu, B., Wang, Y., Zhen, M. and Derry, W.B. The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans . Cell Death and Differentiation 15 (6): 1054-1062.

Wang, W., Bouhours, M., Gracheva, E.O., Liao, E., Xu, K., Sengar, A., Xin, X., Roder, J., Boone, C., Richmond, J., Zhen, M. and Egan. S. ITSN-1 Controls Vesicle Recycling at the Neuromuscular Junction and Functions in Parallel with DAB-1. Traffic 9(5): 742–754.

Kim, J.S.M. and Zhen, M.* Protons as intracellular messengers. Cell 132: 1-22.

Kim, J.S.M. and Zhen, M.* Neuronal polarity. Encyclopedia of Neuroscience, Springer-Verlag.

2007

Hung, W., Hwang, C., Po, M. and Zhen, M.* Neuronal polarity is regulated by a direct interaction between a scaffolding protein Neurabin and a presynaptic SAD-1 kinase in Caenorhabditis elegans . Development 134: 237-249.

2006

Patel, M., Lehrman, E., Poon, V., Crump, J.G., Zhen, M. , Bargmann, C.I., and Shen, K. Hierarchical assembly of presynaptic components in defined C. elegans synapses. Nature Neuroscience 9: 1488-1498.

Wang, Y., Gracheva, E.O., Richmond, J., Kawano, T., Couto, J.M., Calarco, J., Vijayaratnam, V., Jin, Y. and Zhen, M.* The C2H2 zinc-finger protein SYD-9 is a putative post-transcriptional regulator for synaptic transmission. Proceedings in the National Academy of Science USA 103(27): 10450-10455 .

Bi, G.Q., Zhen, M. ,* et al. Recent advances in basic neurosciences and brain disease: from synapses to behaviour. Molecular Pain : 2:38.

Zhen, M.* Presynaptic differentiation. In Protein Trafficking in the Neuron . (A.J. Bean, Ed.) London: Elsevier Academic Press . Page 75-96.

1996-2005

Yeh, E., Kawano, T., Weimer, R., Bessereau, J.L. and Zhen, M.* (2005) Identifying genes involved in synaptogenesis using a fluorescent active zone marker in C. elegans. Journal of Neuroscience 25(15): 3833-3841.

Liao, E., Hung, W., Abrams, B. and Zhen, M.* (2004) An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Nature 430: 345-350.

Zhen, M.* and Jin, Y.* (2004) Presynaptic terminal differentiation: transport and assembly. Current Opinion in Neurobiology 14(3): 280-287.

Crump, J.C., Zhen, M. , Jin, Y. and Bargmann, C.I. (2001) The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination. Neuron 29: 115-129.

Zhen, M. , Huang, X., Bamber, B. and Jin, Y. (2000) Regulation of presynaptic terminal organization by C.elegans RPM-1, a putative guanine nucleotide exchanger with a Ring-H2 finger domain. Neuron 26: 331-343.

Zhen, M. and Jin, Y. (1999) The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401: 371-37.

Zhen, M. , Schein, J.E., Baillie, D.L. and Candido, E.P.M. (1996) An essential ubiquitin-conjugating enzyme with tissue and developmental specificity in the nematode Caenorhabditis elegans . EMBO J . 15: 3229-3237.

Under review:

Adam D. Norris, Shangbang Gao, Megan L. Norris, Debashish Ray, Arun K. Ramani, Andrew G. Fraser, Quaid Morris, Timothy R. Hughes, Mei Zhen and John A. Calarco (2014) Combinatorial control of exon networks in distinct neurons modulates synaptic transmission and behavior. Molecular Cell

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