Mei Zhen

faculty_img Academic Title: Professor

Campus: St. George

CSB Appointment: Cross Appointment

Primary Undergraduate Department: Molecular Genetics

Graduate Programs:
Neuroscience
Physiology

Academic or Administrative Appointments:

Education:
PhD University of British Columbia, 1996

Mailing Address
Mount Sinai Hospital,
600 University Avenue, Room 870,
Toronto, Ontario,
M5G 1X5.

 

Contact Information
Office phone: 416-586-1592
Office: 870
Lab phone: 416-586-4800 ext 6138
Email: zhen@lunenfeld.ca
URL: https://www.zhenlab.com

 

Research Areas

Neurobiology
Developmental Biology
Systems Biology
Genetics
Quantitative Biology
Bioinformatics and Computational Biology

 

Research

Our research addresses how neural circuits develop and operate to generate behaviours. Using C. elegans, an invertebrate model, we seek conserved mechanisms that govern the anatomic assembly of a nervous system, and extract fundamental principles that underlie circuit dynamics – the underpinning of the stereotype and plasticity of behaviors.

We combine cutting-edge technologies, including RNA sequencing, electron microscopy, optogenetics, whole-brain calcium imaging, and electrophysiology, to address three main questions.

1) How does the sensorimotor circuit develop? Neurons are wired through synapses. During development, these connections undergo changes. C. elegans has a small number of neurons, permitting visualization and mechanistic dissection of precise connectivity changes at single synapse level, in the context of an intact, developing nervous system. We apply a cutting edge electron microscopy platform to reconstruct circuit changes at different developmental stages.

2) How does the motor circuit generate movements? Through recording neuronal activity by calcium imaging, quantifying the behavioural changes induced by genetic and optogenetic manipulation of specific neurons, and defining the nature of neuronal communication by electrophysiology, we assign the function of specific neurons and its connectivity in the context of behaviors.

3) What is the underlying circuit deficit of neurological disorders? Through examining genetic mutants with specific sensorimotor behavioural deficit, we have identified neuronal signalling regulators that are causative for neurological disorders. We apply the developed tools for quantitative and functional assessment of neurons, synapses, circuits and behaviors to pinpoint the underlying cellular and circuit defects of these disease models.

 

Publications

 

 

2018

Top

Descending pathway facilitates undulatory wave propagation in Caenorhabditis elegans through gap junctions. Xu T, Huo J, Shao S, Po M, Kawano T, Lu Y, Wu M, Zhen M, Wen Q. Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4493-E4502. doi: 10.1073/pnas.1717022115. Epub 2018 Apr 23.
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The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans. Chitturi J, Hung W, Rahman AMA, Wu M, Lim MA, Calarco J, Baran R, Huang X, Dennis JW, Zhen M. PLoS Genet. 2018 Apr 12;14(4):e1007303. doi: 10.1371/journal.pgen.1007303. eCollection 2018 Apr.
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Excitatory motor neurons are local oscillators for backward locomotion. Gao S, Guan SA, Fouad AD, Meng J, Kawano T, Huang YC, Li Y, Alcaire S, Hung W, Lu Y, Qi YB, Jin Y, Alkema M, Fang-Yen C, Zhen M. Elife. 2018 Jan 23;7. pii: e29915. doi: 10.7554/eLife.29915.
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2017

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UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans. Park S, Bin NR, Yu B, Wong R, Sitarska E, Sugita K, Ma K, Xu J, Tien CW, Algouneh A, Turlova E, Wang S, Siriya P, Shahid W, Kalia L, Feng ZP, Monnier PP, Sun HS, Zhen M, Gao S, Rizo J, Sugita S. J Neurosci. 2017 Sep 6;37(36):8797-8815. doi: 10.1523/JNEUROSCI.0338-17.2017. Epub 2017 Aug 8.pubmed
The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development. Opperman KJ, Mulcahy B, Giles AC, Risley MG, Birnbaum RL, Tulgren ED, Dawson-Scully K, Zhen M, Grill B. Cell Rep. 2017 Apr 25;19(4):822-835. doi: 10.1016/j.celrep.2017.04.003.pubmed
Myrf ER-Bound Transcription Factors Drive C. elegans Synaptic Plasticity via Cleavage-Dependent Nuclear Translocation. Meng J, Ma X, Tao H, Jin X, Witvliet D, Mitchell J, Zhu M, Dong MQ, Zhen M, Jin Y, Qi YB. Dev Cell. 2017 Apr 24;41(2):180-194.e7. doi: 10.1016/j.devcel.2017.03.022.pubmed
Correction: Neuroendocrine modulation sustains the C. elegans forward motor state. Lim M, Chitturi J, Laskova V, Meng J, Findeis D, Wiekenberg A, Mulcahy B, Luo L, Li Y, Lu Y, Hung W, Qu Y, Ho C, Holmyard D, Ji N, McWhirter RD, Samuel AD, Miller DM, Schnabel R, Calarco JA, Zhen M. Elife. 2017 Mar 8;6. pii: e26528. doi: 10.7554/eLife.26528.pubmed
 

2016

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A hybrid microfluidic device for on-demand orientation and multidirectional imaging of C. elegans organs and neurons. Ardeshiri R, Mulcahy B, Zhen M, Rezai P. Biomicrofluidics. 2016 Dec 1;10(6):064111. eCollection 2016 Nov.
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Filling the gap: adding super-resolution to array tomography for correlated ultrastructural and molecular identification of electrical synapses at the C. elegans connectome. Markert SM, Britz S, Proppert S, Lang M, Witvliet D, Mulcahy B, Sauer M, Zhen M, Bessereau JL, Stigloher C. Neurophotonics. 2016 Oct;3(4):041802. doi: 10.1117/1.NPh.3.4.041802. Epub 2016 May 4.
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Pan-neuronal imaging in roaming Caenorhabditis elegans. Venkatachalam V, Ji N, Wang X, Clark C, Mitchell JK, Klein M, Tabone CJ, Florman J, Ji H, Greenwood J, Chisholm AD, Srinivasan J, Alkema M, Zhen M, Samuel AD.Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E1082-8. doi: 10.1073/pnas.1507109113. Epub 2015 Dec 28.
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Conformational states of syntaxin-1 govern the necessity of N-peptide binding in exocytosis of PC12 cells and Caenorhabditis elegans. Park S, Bin NR, Michael Rajah M, Kim B, Chou TC, Kang SY, Sugita K, Parsaud L, Smith M, Monnier PP, Ikura M, Zhen M, Sugita S. Mol Biol Cell. 2016 Feb 15;27(4):669-85. doi: 10.1091/mbc.E15-09-0638. Epub 2015 Dec 23.
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2015

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ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function. Murakami T, Qamar S, Lin JQ, Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FT, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Favrin G, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop P. Neuron. 2015 Nov 18;88(4):678-90. doi: 10.1016/j.neuron.2015.10.030. Epub 2015 Oct 29.
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C. elegans locomotion: small circuits, complex functions. Zhen M, Samuel AD. Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12167-72. doi: 10.1073/pnas.1018832108. Curr Opin Neurobiol. 2015 Aug;33:117-26. doi: 10.1016/j.conb.2015.03.009. Epub 2015 Apr 4.
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A Gain-of-Function Mutation in NALCN in a Child with Intellectual Disability, Ataxia, and Arthrogryposis. Aoyagi K, Rossignol E, Hamdan FF, Mulcahy B, Xie L, Nagamatsu S, Rouleau GA6, Zhen M, Michaud JL. Hum Mutat. 2015 Aug;36(8):753-7. doi: 10.1002/humu.22797. Epub 2015 Jun 22.
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MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses through Neuroligin. Maro GS, Gao S, Olechwier AM, Hung WL, Liu M, Özkan E, Zhen M, Shen K. Neuron. 2015 Jun 17;86(6):1420-32. doi: 10.1016/j.neuron.2015.05.015. Epub 2015 May 28.
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The C. elegans COE transcription factor UNC-3 activates lineage-specific apoptosis and affects neurite growth in the RID lineage. Wang J, Chitturi J, Ge Q, Laskova V, Wang W, Li X, Ding M, Zhen M, Huang X. Development. 2015 Apr 15;142(8):1447-57. doi: 10.1242/dev.119479. Epub 2015 Mar 19.
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CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling. Lant B, Yu B, Goudreault M, Holmyard D, Knight JD, Xu P, Zhao L, Chin K, Wallace E, Zhen M, Gingras AC, Derry WB. Nat Commun. 2015 Mar 6;6:6449. doi: 10.1038/ncomms7449.
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The NCA sodium leak channel is required for persistent motor circuit activity that sustains locomotion. Gao S, Xie L, Kawano T, Po MD, Guan S, Zhen M, Pirri JK, Alkema MJ. Nat Commun. 2015 Feb 26;6:6323. doi: 10.1038/ncomms7323.
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2014

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A pair of RNA-binding proteins controls networks of splicing events contributing to specialization of neural cell types. Norris AD, Gao S, Norris ML, Ray D, Ramani AK, Fraser AG, Morris Q, Hughes TR, Zhen M, Calarco JA. Mol Cell. 2014 Jun 19;54(6):946-59. doi: 10.1016/j.molcel.2014.05.004. Epub 2014 Jun 5.
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2013

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A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication. Hung WL, Wang Y, Chitturi J, Zhen M. Development. 2014 Apr;141(8):1767-79. doi: 10.1242/dev.103846. Epub 2014 Mar 26.
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Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. Hung WL, Hwang C, Gao S, Liao EH, Chitturi J, Wang Y, Li H, Stigloher C, Bessereau JL, Zhen M. EMBO J. 2013 Jun 12;32(12):1745-60. doi: 10.1038/emboj.2013.91. Epub 2013 May 10.
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Hyperactivation of B-type motor neurons results in aberrant synchrony of the Caenorhabditis elegans motor circuit. Qi YB, Po MD, Mac P, Kawano T, Jorgensen EM, Zhen M, Jin Y. J Neurosci. 2013 Mar 20;33(12):5319-25. doi: 10.1523/JNEUROSCI.4017-12.2013.
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NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion. Xie L, Gao S, Alcaire SM, Aoyagi K, Wang Y, Griffin JK, Stagljar I, Nagamatsu S, Zhen M. Neuron. 2013 Mar 20;77(6):1069-82. doi: 10.1016/j.neuron.2013.01.018.
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2012

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Proprioceptive coupling within motor neurons drives C. elegans forward locomotion.Wen Q, Po MD, Hulme E, Chen S, Liu X, Kwok SW, Gershow M, Leifer AM, Butler V, Fang-Yen C, Kawano T, Schafer WR, Whitesides G, Wyart M, Chklovskii DB, Zhen M, Samuel AD. Neuron. 2012 Nov 21;76(4):750-61. doi: 10.1016/j.neuron.2012.08.039.
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Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development. Najarro EH, Wong L, Zhen M, Carpio EP, Goncharov A, Garriga G, Lundquist EA, Jin Y, Ackley BD. J Neurosci. 2012 Mar 21;32(12):4196-211. doi: 10.1523/JNEUROSCI.3094-11.2012.
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Releasing the inner inhibition for axon regeneration. Po MD, Calarco JA, Zhen M. Neuron. 2012 Jan 26;73(2):207-9. doi: 10.1016/j.neuron.2012.01.002.
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ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.Murakami T, Yang SP, Xie L, Kawano T, Fu D, Mukai A, Bohm C, Chen F, Robertson J, Suzuki H, Tartaglia GG, Vendruscolo M, Kaminski Schierle GS, Chan FT, Moloney A, Crowther D, Kaminski CF, Zhen M, St George-Hyslop P. Hum Mol Genet. 2012 Jan 1;21(1):1-9. doi: 10.1093/hmg/ddr417. Epub 2011 Sep 23.
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2011

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An imbalancing act: gap junctions reduce the backward motor circuit activity to bias C. elegans for forward locomotion. Kawano T, Po MD, Gao S, Leung G, Ryu WS, Zhen M. Neuron. 2011 Nov 17;72(4):572-86. doi: 10.1016/j.neuron.2011.09.005.
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Mutations in a guanylate cyclase GCY-35/GCY-36 modify Bardet-Biedl syndrome-associated phenotypes in Caenorhabditis elegans. Mok CA, Healey MP, Shekhar T, Leroux MR, Héon E, Zhen M. PLoS Genet. 2011 Oct;7(10):e1002335. doi: 10.1371/journal.pgen.1002335. Epub 2011 Oct 13.
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The dystrophin-associated protein complex maintains muscle excitability by regulating Ca(2+)-dependent K(+) (BK) channel localization. Sancar F, Touroutine D, Gao S, Oh HJ, Gendrel M, Bessereau JL, Kim H, Zhen M, Richmond JE. J Biol Chem. 2011 Sep 23;286(38):33501-10. doi: 10.1074/jbc.M111.227678. Epub 2011 Jul 27.
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Networking in a global world: establishing functional connections between neural splicing regulators and their target transcripts. Calarco JA, Zhen M, Blencowe BJ. RNA. 2011 May;17(5):775-91. doi: 10.1261/rna.2603911. Epub 2011 Mar 17.
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A co-operative regulation of neuronal excitability by UNC-7 innexin and NCA/NALCN leak channel. Bouhours M, Po MD, Gao S, Hung W, Li H, Georgiou J, Roder JC, Zhen M. Mol Brain. 2011 Apr 13;4:16. doi: 10.1186/1756-6606-4-16.
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The presynaptic dense projection of the Caenorhabditis elegans cholinergic neuromuscular junction localizes synaptic vesicles at the active zone through SYD-2/liprin and UNC-10/RIM-dependent interactions. Stigloher C, Zhan H, Zhen M, Richmond J, Bessereau JL. J Neurosci. 2011 Mar 23;31(12):4388-96. doi: 10.1523/JNEUROSCI.6164-10.2011.
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Lack of association of NALCN genetic variants with schizophrenia. Souza RP, Rosa DV, Romano-Silva MA, Zhen M, Meltzer HY, Lieberman JA, Remington G, Kennedy JL, Wong AH. Psychiatry Res. 2011 Feb 28;185(3):450-2. doi: 10.1016/j.psychres.2010.07.009. Epub 2010 Jul 31.
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Action potentials drive body wall muscle contractions in Caenorhabditis elegans. Gao S, Zhen M. Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2557-62. doi: 10.1073/pnas.1012346108. Epub 2011 Jan 19.
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Genome-wide analysis of alternative splicing in Caenorhabditis elegans. Ramani AK, Calarco JA, Pan Q, Mavandadi S, Wang Y, Nelson AC, Lee LJ, Morris Q, Blencowe BJ, Zhen M, Fraser AG. Genome Res. 2011 Feb;21(2):342-8. doi: 10.1101/gr.114645.110. Epub 2010 Dec 22.
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2010

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The long and the short of SAD-1 kinase. Kim JS1, Hung W, Zhen M. Commun Integr Biol. 2010 May;3(3):251-5.
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PHRs: bridging axon guidance, outgrowth and synapse development. Po MD, Hwang C, Zhen M. Curr Opin Neurobiol. 2010 Feb;20(1):100-7. doi: 10.1016/j.conb.2009.12.007. Epub 2010 Jan 14.
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Ciliary dysfunction and obesity. Mok CA, Héon E, Zhen M. Clin Genet. 2010 Jan;77(1):18-27. doi: 10.1111/j.1399-0004.2009.01305.x. Epub 2009 Nov 20.
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C. elegans STRADalpha and SAD cooperatively regulate neuronal polarity and synaptic organization. Kim JS, Hung W, Narbonne P, Roy R, Zhen M. Development. 2010 Jan;137(1):93-102. doi: 10.1242/dev.041459.
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2009

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Regulation of vertebrate nervous system alternative splicing and development by an SR-related protein. Calarco JA, Superina S, O’Hanlon D, Gabut M, Raj B, Pan Q, Skalska U, Clarke L, Gelinas D, van der Kooy D, Zhen M, Ciruna B, Blencowe BJ. Cell. 2009 Sep 4;138(5):898-910. doi: 10.1016/j.cell.2009.06.012.
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Caenorhabditis elegans innexins regulate active zone differentiation. Yeh E, Kawano T, Ng S, Fetter R, Hung W, Wang Y, Zhen M. J Neurosci. 2009 Apr 22;29(16):5207-17. doi: 10.1523/JNEUROSCI.0637-09.2009.
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2008

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Optogenetic analysis of synaptic function. Liewald JF, Brauner M, Stephens GJ, Bouhours M, Schultheis C, Zhen M, Gottschalk A. Nat Methods. 2008 Oct;5(10):895-902. doi: 10.1038/nmeth.1252. Epub 2008 Sep 14.
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A chemical-genetic strategy reveals distinct temporal requirements for SAD-1 kinase in neuronal polarization and synapse formation. Kim JS, Lilley BN, Zhang C, Shokat KM, Sanes JR, Zhen M. Neural Dev. 2008 Sep 22;3:23. doi: 10.1186/1749-8104-3-23.
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The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans. Gao MX, Liao EH, Yu B, Wang Y, Zhen M, Derry WB. Cell Death Differ. 2008 Jun;15(6):1054-62. doi: 10.1038/cdd.2008.30. Epub 2008 Mar 14.
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ITSN-1 controls vesicle recycling at the neuromuscular junction and functions in parallel with DAB-1. Wang W, Bouhours M, Gracheva EO, Liao EH, Xu K, Sengar AS, Xin X, Roder J, Boone C, Richmond JE, Zhen M, Egan SE. Traffic. 2008 May;9(5):742-54. doi: 10.1111/j.1600-0854.2008.00712.x. Epub 2008 Feb 20.
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An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes. Li C, Inglis PN, Leitch CC, Efimenko E, Zaghloul NA, Mok CA, Davis EE, Bialas NJ, Healey MP, Héon E, Zhen M, Swoboda P, Katsanis N, Leroux MR. PLoS Genet. 2008 Mar 28;4(3):e1000044. doi: 10.1371/journal.pgen.1000044.
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A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans. Yeh E, Ng S, Zhang M, Bouhours M, Wang Y, Wang M, Hung W, Aoyagi K, Melnik-Martinez K, Li M, Liu F, Schafer WR, Zhen M. PLoS Biol. 2008 Mar 11;6(3):e55. doi: 10.1371/journal.pbio.0060055.
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Protons as intercellular messengers. Kim JS, Zhen M. Cell. 2008 Jan 11;132(1):21-2. doi: 10.1016/j.cell.2007.12.020.
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2007

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Neuronal polarity is regulated by a direct interaction between a scaffolding protein, Neurabin, and a presynaptic SAD-1 kinase in Caenorhabditis elegans. Hung W, Hwang C, Po MD, Zhen M. Development. 2007 Jan;134(2):237-49. Epub 2006 Dec 6.
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2006

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Recent advances in basic neurosciences and brain disease: from synapses to behavior. Bi GQ, Bolshakov V, Bu G, Cahill CM, Chen ZF, Collingridge GL, Cooper RL, Coorssen JR, El-Husseini A, Galhardo V, Gan WB, Gu J, Inoue K, Isaac J, Iwata K, Jia Z, Kaang BK, Kawamata M, Kida S, Klann E, Kohno T, Li M, Li XJ, MacDonald JF, Nader K, Nguyen PV, Oh U, Ren K, Roder JC, Salter MW, Song W, Sugita S, Tang SJ, Tao Y, Wang YT, Woo N, Woodin MA, Yan Z, Yoshimura M, Xu M, Xu ZC, Zhang X, Zhen M, Zhuo M. Mol Pain. 2006 Dec 30;2:38.
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Hierarchical assembly of presynaptic components in defined C. elegans synapses. Patel MR, Lehrman EK, Poon VY, Crump JG, Zhen M, Bargmann CI, Shen K. Nat Neurosci. 2006 Dec;9(12):1488-98. Epub 2006 Nov 19.
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The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission. Wang Y, Gracheva EO, Richmond J, Kawano T, Couto JM, Calarco JA, Vijayaratnam V, Jin Y, Zhen M. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10450-10455. doi: 10.1073/pnas.0602073103. Epub 2006 Jun 27.
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2005

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Identification of genes involved in synaptogenesis using a fluorescent active zone marker in Caenorhabditis elegans. Yeh E, Kawano T, Weimer RM, Bessereau JL, Zhen M. J Neurosci. 2005 Apr 13;25(15):3833-41.
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2004

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An SCF-like ubiquitin ligase complex that controls presynaptic differentiation. Liao EH, Hung W, Abrams B, Zhen M. Nature. 2004 Jul 15;430(6997):345-50. Epub 2004 Jun 20.
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Presynaptic terminal differentiation: transport and assembly. Zhen M, Jin Y. Curr Opin Neurobiol. 2004 Jun;14(3):280-7.
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2001

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The SAD-1 kinase regulates presynaptic vesicle clustering and axon termination. Crump JG, Zhen M, Jin Y, Bargmann CI. Neuron. 2001 Jan;29(1):115-29.
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2000

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Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain. Zhen M, Huang X, Bamber B, Jin Y. Send to
Neuron. 2000 May;26(2):331-43.
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1999

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The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Zhen M, Jin Y. Nature. 1999 Sep 23;401(6751):371-5.
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1996

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An essential ubiquitin-conjugating enzyme with tissue and developmental specificity in th nematode Caenorhabditis elegans. Zhen M, Schein JE, Baillie DL, Candido EP. EMBO J. 1996 Jul 1;15(13):3229-37.
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1993

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The ubc-2 gene of Caenorhabditis elegans encodes a ubiquitin-conjugating enzyme involved in selective protein degradation. Zhen M, Heinlein R, Jones D, Jentsch S, Candido EP. Mol Cell Biol. 1993 Mar;13(3):1371-7.
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