Director, Cleveland Brain Health Initiative
The brain contains billions of nerve cells (i.e., neurons) which receive and integrate signals from the environment and govern the body's responses. This is made possible by synapses - contacts between neurons or between a neuron and a target cell such as muscles. As such, synapses are fundamental units of the neural circuitry and enable complex behaviors. We investigate mechanisms of synapse formation and function and how synapses go wrong in brain disorders.
One model we use is the neuromuscular junction (NMJ), a peripheral synapse formed between motoneurons and muscle fibers that is critical for muscle contraction. This traditional chemical synapse has served as an informative model of synapse structure and function. The NMJ formation requires agrin, a trophic factor from motoneurons and MuSK, a transmembrane tyrosine kinase. We together with our colleagues identified LRP4 as a receptor for agrin and revealed mechanisms how signals are transduced from agrin to MuSK by solving the crystal structure of an agrin-LRP4 complex. We demonstrated that rapsyn, a classic adapter protein critical to the NMJ, serves also as an enzyme whose enzymatic activity is required for NMJ formation. Recently, we found that rapsyn undergoes liquid-liquid phase separation to form membrane-less condensates, a platform for signaling for NMJ structure and function. Our studies also revealed novel pathways that regulate the development, maintenance, and regeneration of the NMJ. We and colleagues have discovered antibodies against LRP4 and agrin in patients with myasthenia gravis and demonstrated that they are causal to myasthenia gravis. The antibodies are now used as novel biomarkers for diagnosis of myasthenia gravis. Finally, we and colleagues demonstrated that increasing the agrin-LRP4-MuSK signaling is beneficial in preventing NMJ decline in ageing and neuromuscular disorders.
In another line of research, we aim at uncovering physiological functions and pathological mechanisms of risk genes of brain disorders including schizophrenia, autism, and major depression. They include Cullin 3, TMEM108, erbin, and neuregulin 1 and its receptor ErbB4. We and colleagues have demonstrated that NRG1 and ErbB4 are not only critical to the development of inhibitory (GABAergic) circuits, but also to maintaining GABAergic transmission in the brain. We discovered that NRG1 is produced by pyramidal neurons in activity-dependent manner; and it binds to ErbB4 in interneurons to promote or maintain GABA transmission, and consequently suppresses the activity of pyramidal neurons. This feed-back mechanism appears to regulate local and inter-regional synchrony of neuron activity and brain functions including working memory, fear, and attention.
Currently, we are actively pursuing the two lines of research by using innovative technologies (genetically manipulated mouse models, optogenetics, in vivo recording with multi-electrodes and calcium imaging in free-moving mice, viral tracing, omic analysis and single cell sequencing). Our studies should contribute to a better understanding of how the brain works and help to identify new leads for potential therapeutic strategies for neuromuscular disorders including ALS, SMA, myasthenia gravis, and psychiatric disorders such as schizophrenia, autism, and depression.
For Dr. Lin Mei's Featured Research and News
Selected Recent Publications
Z. Tan, Z. Liu, Y. Liu, F. Liu, H. Robinson, T.W. Lin, W.-C. Xiong, and L. Mei. An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction. J. Neurosci. (in press)
H. Wang, W. Chen, Z. Dong, G. Xing, W. Cui, L. Yao, W.-J. Zou, H.L. Robinson, Y. Bian, Z. Liu, K. Zhao, B. Luo, N. Gao, H. Zhang, X. Ren, Z. Yu, J. Meixiong, W.-C. Xiong, and L. Mei. A novel spinal neuron connection for heat sensation. Neuron 110:2315-2333, 2022.
H.L. Robinson, Z. Tan, I. Santiago-Marrero, E.P. Arzola, Timothy Dong, W.-C. Xiong, L. Mei. Neuregulin 1 and ErbB4 kinase actively regulate sharp wave ripples in the hippocampus. Journal of Neuroscience 2022 Jan 19;42(3):390-404. (Cover)
Z. Yu, M. Zhang, H. Jing, P. Chen, R. Cao, P. Pan, B. Luo, Y. Yu, B.M. Quarles, W.C. Xiong, M.H. Rivner, and L. Mei. Characterization of LRP4/agrin Antibodies from a Patient with Myasthenia Gravis. Neurology 2021 Sep 7;97(10):e975-e987. [Preview by Lisak, Neurology Sep 07, 2021; 97 (10)]
W. Cui, N. Gao, Z. Dong, C. Shen, H. Zhang, B. Luo, P. Chen, D. Comoletti, H. Jing, H. Wang, H. Robinson, W.C. Xiong, and L. Mei. In-trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development. Current Biology 2021 Aug 9;31(15):3330-3342.e7.
G. Xing, H. Jing, Z. Yu, P. Chen, H. Wang, W.C Xiong, and L. Mei. Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron 2021 Jun 16;109:1963-1978.e5. (Preview by Bai and Zhang, Neuron, 109:1907-1909, 2021) (Cover)
H. Wang, W. Cui, W. Chen, F. Liu, Z. Dong, G. Xing, B. Luo, N. Gao, W.-J. Zou, K. Zhao, H. Zhang, X. Ren, Z. Yu, H.L. Robinson, Z. Liu, W.C. Xiong, L. Mei. The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons. Molecular Psychiatry 2021 May 14;.
W.B. Chen*, B. Luo*, N.N. Gao*, H.W. Li, H.S. Wang, L. Li, W.P. Cui, L. Zhang, D. Sun, F. Liu, Z.Q. Dong, X. Ren, H.S. Zhang, H. B. Su, W.C. Xiong, and L. Mei. Neddylation stabilizes Nav1.1 to maintain interneuron excitability and prevent seizures in murine epilepsy models. J. Clin. Invest. 2021 Apr 15;131(8). (Commentary by S.C. Cannon, Epilepsy channelopathies go neddy: stabilizing NaV1.1 channels by neddylation. J. Clin. Invest. 131(8):e148370., 2021)
Z. Dong*, W. Chen*, C. Chen, H. Wang, W. Cui, Z. Tan, H. Robinson, N. Gao, B. Luo, L. Zhang, K. Zhao, W.C. Xiong and L. Mei. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron 105: 475-490, 2020 (Cover; Preview by Chen & Maher, Neuron, 105:398-399, 2020).
H. Zhang, W. Chen, Z. Tan, L. Zhang, Z. Dong, W. Cui, K. Zhao, H. Wang, H. Jing, R. Cao, C. Kim, J.G. Safar, W.-C. Xiong and L. Mei. A role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance. J. Neurosci., 40:5347:5361, 2020
N. Gao, K. Zhao, Y. Cao, X. Ren, H. Jing, G. Xing, W.-C. Xiong, and Lin Mei. A role of lamin A/C in preventing neuromuscular junction decline in mice. J. Neurosci. 40:7203-7215, 2020 (Cover)
M.H. Rivner, B.M. Quarles, J.-X. Pan, Z. Yu, J.F. Howard Jr, A. Corse, M.M. Dimachkie, C. Jackson, T. Vu, G. Small, R.P. Lisak, J. Belsh, I. Lee, R.J. Nowak, V. Baute, S. Scelsa, J.A. Fernandes, Z. Simmons, A. Swenson, R. Barohn, R.B. Sanka, C. Gooch, E. Ubogu, J. Caress, M. Pasnoor, H. Xu, L. Mei. Clinical features of LRP4/agrin-antibody – positive myasthenia gravis: A multicenter study. Muscle & Nerve 62:333–343, 2020.
L. Zhang, H. Jing, H. Li, W. Chen, B. Luo, H-S. Zhang, Z-Q. Dong, L. Li, H-B. Su, W-C. Xiong and L. Mei. Neddylation is critical to cortical development by regulating Wnt/b-catenin signaling. Proc. Nat. Acad. Sci. USA. 117:26448-26459, 2020
G. Xing, H. Jing, L. Zhang, Y. Cao, L. Li, K. Zhao, Z. Dong, W. Chen, H. Wang, R. Cao, W.C. Xiong, and L. Mei. A mechanism in agrin signaling revealed by a prevalent rapsyn mutation in congenital myasthenic syndrome. eLife 8:e49180, 2019
H. Zhang, A. Sathyamurthy, F. Liu, L. Li, L. Zhang, Z. Dong, W. Cui, X. Sun, K. Zhao, H. Wang, H.-Y. H. Ho, W.C. Xiong, L. Mei. Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice. eLife 8:e45303, 2019
H. Wang,* F. Liu,* W. Chen,* X. Sun, W. Cui, Z. Dong, K. Zhao, H. Zhang, H. Li, G. Xing, E. Fei, B.-X. Pan, B.-M. Li, W.-C. Xiong, Lin Mei. Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice. PNAS 115:13105-13110, 2018
K. Zhao*, C. Shen,*,** L. Li, H. Wu, G. Xing, Z. Dong, W. Chen, H. Zhang, J. Pan, H. Wang, W. Cui, X.D. Sun, S. Li, X. Li, X. Huang, W.C. Xiong, and L. Mei**. Sarcoglycan Alpha Mitigation of Neuromuscular Junction Decline in Aged Mice by Stabilizing Lrp4. J. Neurosci. (Front Cover Work, 38 (41) 8860-8873, 2018) *, equal contributing; **, co-corresponding.
X.-D. Sun*,**, W.-B. Chen**, D. Sun**, J. Huang, Y.-Q. Li, J.-X. Pan, Y.-N. Wang, K. Zhao, Z.-Q. Dong, H.-S. Wang, L. Xiong, A. Xuan, S.-T. Zhao, A. Pillai, W.-C. Xiong* and L. Mei. Neogenin in amygdala for neuronal activity and fear memory. J. Neuroscience. J. Neurosci. 38 (44) 9600-9613. (*, co-corresponding; **, co-first)
C. Shen*,**, L. Li**, K. Zhao**, L. Bai, A. Wang, X. Shu, Y. Xiao, J. Zhang, K. Zhang, T. Hui, W. Chen, B. Zhang, W. Hsu, W.-C. Xiong, L. Mei*. Motoneuron Wnts regulate neuromuscular junction development. eLife. 7, 2018 (*, co-corresponding; **, co-first)
Y.-N. Wang, D. Figueiredo, X.-D. Sun, Z.-Q. Dong, W.-B. Chen, W.-P. Cui, F. Liu, H.-S. Wang, H.-W. Li, H. Robinson, E.-K. Fei, B.-X. Pan, B-M Li, W-C Xiong and L. Mei. Controlling of glutamate release by neuregulin3 via inhibiting the assembly of SNARE-complex. Proc. Nat. Acad. Sci. 115:2508-2513, 2018.
T.W. Lin, Z. Tan, A. Barik, D. Yin, E. Brudvik, H. Wang, W.C. Xiong, L. Mei. Regulation of Synapse Development by Vgat Deletion from ErbB4-Positive Interneurons. J. Neurosci. 38:2533-2550, 2018.
M. Yan, Z. Liu, E. Fei, W. Chen, X. Lai, B. Luo, P. Chen, H. Jing, J. Pan, M. Rinver, W.C. Xiong, and L. Mei. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience, 373:113-121, 2018.
Z. Tan, H. Robinson, D. Yin, Y. Liu, F. Liu, H. Wang, T.W. Lin, G. Xing, W.C. Xiong, L. Mei. Dynamic ErbB4 Activity in Hippocampal-Prefrontal Synchrony and Top-Down Attention in Rodents. Neuron, 98:380-393, 2018.
H.F. Jiao*, X.D. Sun*, R. Bates*, L. Xiong, F. Liu, L. Li, H.S. Zhang, S.Q. Wang, M.T. Xiong, M. Patel, A.M. Stranahan, W.C. Xiong, B.M. Li#, L. Mei#. Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus. Proc. Nat. Acad. Sci. USA. 114: 1177-1182, 2017
(*, equal contributing; #, equal corresponding).
K. Zhao, C. Shen, Y. Lu, Z. Huang, L. Li, C.D. Rand, J. Pan, X.D. Sun, Z. Tan, H. Wang, G. Xing, Y. Cao, W.C. Xiong, and L. Mei. Muscle Yap is a regulator of neuromuscular junction formation and regeneration. J. Neuroscience 37:3465-3477, 2017 (Cover). (Highlighted by Faculty 1000, DOI: 10.3410/f.727317699.793531488).
Li,* Y. Cao,* H. Wu, X. Ye, Z. Zhu, G. Xing, C. Shen, A. Barik, B. Zhang, X. Xie, W. Zhi, L. Gan, H. Su, W.C. Xiong, L. Mei. Enzymatic activity of the scaffold protein rapsyn for synapse formation. Neuron. 2016 Dec 7;92(5):1007-1019. Epub 2016 Nov 10. (*, equal contributing).
H. Wu*, A. Barik*, Y. Lu, C. Shen, A. Bowman, L. Li, A. Sathyamurthy, T.W. Lin, W.C. Xiong, and L. Mei. Slit2 as a β-catenin/Ctnnb1-dependent retrograde signal for presynaptic differentiation. eLife 4:e07266, 2015 (*, co-first).
X.D. Sun,*,** L. Li*, F. Liu, Z.H. Huang, J.C. Bean, H.F. Jiao, A. Barik, S.M. Kim, H. Wu, Shen, Y. Tian, T.W. Lin, R. Bates, A. Sathyamurthy, Y.J. Chen, D.M. Yin, L. Xiong, H.P. Lin, J.X. Hu, B.M. Li, T.M. Gao, W.C. Xiong, Lin Mei**. Lrp4 in astrocytes modulates glutamatergic transmission. Nature Neuroscience 19:1010-1018, 2016 (*, equal contributing; **, corresponding).
A. Barik, L. Li, A. Sathyamurthy, W.-C. Xiong and L. Mei. Schwann Cells in Neuromuscular Junction Formation and Maintenance. J. Neurosci., 36:9770-9781, 2016 (Cover)
Lu,* X.-D. Sun,* F.-Q. Hou, F. Liu, L.L. Bi, D.M. Yin, Y.J. Chen, J. Bean, H.F. Jiao, X. Liu, B.M. Li, W.C. Xiong, T.M. Gao** and L. Mei**. Maintenance of GABAergic activity by neuregulin 1/ErbB4 in amygdala for fear conditioning memory. Neuron 84:835-846, 2014. (*, co-first; **, co-correspondent).
A. Barik, Y. Lu, A. Sathyamurthy, A. Bowman, C. Shen, L. Li, W.-C. Xiong and L. Mei. LRP4 Is Critical for Neuromuscular Junction Maintenance. J.Neurosci. 34:13892-13905, 2014 (Cover)
C. Shen*, B. Zhang*, Y. Lu*, D. Figueiredo, H. Wu, B. Arnab, W.C. Xiong and L. Mei. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J. Clin. Invest. 123:5190–5202, 2013.
D.M. Yin*, Y.J. Chen*, Y.S. Lu, J.C. Bean, A. Sathyamurthy, C.Y. Shen, X.H. Liu, T.W. Lin, C.A. Smith, W.C. Xiong, and L. Mei. Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. Neuron 78:644-657, 2013.
(Highlighted by Preview, Neuron 78:577, 2013) PMID: 23719163.
Y. Tao*, Y. Chen*, C. Shen*, Z. Luo, C.R. Bates, D. Lee, S. Marchetto, T.-M. Gao, J.-P. Borg, W.C. Xiong, Lin Mei. Erbin interacts with TARP gamma-2 for surface expression of AMPA receptors in cortical interneurons. Nature Neurosci. 16:290-299, 2013. (*, cofirst).
H.T. Wu, Y.S. Lu, C.Y. Shen, W.C. Xiong, L. Mei. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron, 75:94-107, 2012.
Y. Zong, B. Zhang, S. Gu, K. Lee, J. Zhou, G. Yao, D. Figueiredo, K. Perry, L. Mei* and Rongsheng Jin*. Structural basis of agrin–LRP4–MuSK signaling. Genes & Development. 26:247-258, 2012 (Cover) (*, co-correspondence).
B. Zhang, J.S. Tzartos, M. Belimezi, S. Ragheb, B. Bealmear, R.A. Lewis, W.C. Xiong, R.P. Lisak, S.J. Tzartos, Lin Mei. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis . Archive Neurol. 69:445-451, 2012. (Highlighted by Editorial, same issue, Archive Neurol., 2012).
S. Luo, B. Zhang, X.-p. Dong, Y. Tao, A. Ting, Z. Zhou, J. Meixiong, J. Luo, F.C.A. Chiu, W.C. Xiong, L. Mei. HSP90β Regulates Rapsyn Turnover and Subsequent AChR Cluster Formation and Maintenance. Neuron 60:97-110, 2008.
(Highlighted at Faculty 1000, DOI: 10.3410/f.1141890.598995)
L. Wen1, Y.S. Lu1, X. Zhu1, X.M. Li, R.-S. Woo, Y.-J. Chen, D.-M. Yin, C. Lai, A. Vazdarjanova, W.C. Xiong, and L. Mei. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Nat. Acad. Sci. USA 107:1211- 1216, 2010..
B. Zhang, S. Luo, Q. Wang, T. Suzuki, W.C. Xiong, Lin Mei. LRP4 serves as a coreceptor of agrin. Neuron 60:285-297, 2008 (highlighted in Nature 455:1153, 2008; Nature Rev. Neurosci. 9:886, 2008; Neuron, 60:526, 2008).
R.-S. Woo*, X.M. Li*, Y. Tao, E. Carpenter-Hyland, Y.Z. Huang, J. Weber, H. Neiswender, X..-p. Dong, J. Wu, M. Gassmann, C. Lai, W.-C. Xiong, T.-M. Gao1, L. Mei1. Neuregulin-1 Enhances Depolarization-Induced GABA Release. Neuron 54:599-610, 2007 (Highlighted in Neuron 54:495-497, 2007; Nature 448:263, 2007 and Nature Rev. Neurosci., 8:492, 2007). (*, co-contributing; 1, co-correspondence).
Selected Recent Reviews
E. Arzola, W.-C. Xiong, and L. Mei. Stress reduces extracellular ATP in the prefrontal cortex and activates the PFC-LHb pathway for depressive-like behavior. Biol. Psych. 92:172-174, 2022
H. Wang, W.-C. Xiong, and L. Mei. Excessive mitophagy for anxiety. Neuron 109:3715-3716, 2021
G. Xing, W.C. Xiong, L. Mei. Rapsyn as a signaling and scaffolding molecule in NMJ formation and maintenance. Neurosci. Lett. 731:1350132, 2020
M Yan, GL Xing, WC Xiong, L Mei. Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis. Ann. New York Acad. Sci. 1413: 126-135, 2018.
L. Li, W.C. Xiong, L. Mei, Neuromuscular junction formation, aging, and disorders. Ann. Rev. Physiol. 2018
Mei and K.-A. Nave, A neuregulin and ErbB network in the nervous system. Neuron 83:27-49, 2014
Wu, Wen C. Xiong, L. Mei. To build a synapse: Signaling pathways in neuromuscular junction assembly. Development 137:1017-1033, 2010
Mei and W.C. Xiong, Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Rev. Neurosci. 9:437-452, 2008.