CIMR-Lin Mei

Research Group

Lin Mei

linmei(at)cimrbj.ac.cn

Lab Website

Distinguished Investigator & Director

linmei(at)cimrbj.ac.cn

B.S. in Clinical Medicine Science, Jiangxi Medical College, China

Ph. D. in Pharmacology and Toxicology, University of Arizona, USA

Work Experience

2023-present

Distinguished Investigator & Director, Chinese Institutes for Medical Research, Beijing, China

2023-present

Chair Professor, Capital Medical University, China

2017-2023

Professor and Chair, Department of Neurosciences, Allen C. Holmes Professor, and Inaugural Director, Cleveland Brain Health Initiative (CBHI), Case Western Reserve University School of Medicine, USA

2004-2017

Professor and Georgia Eminent Scholar, Institute of Molecular Medicine and Genetics (as Director, 2009-2014), Medical College of Georgia, Augusta University, and Inaugural Chair of Department of Neuroscience and Regenerative Medicine (2014-2017), USA

1999-2004

Assistant Professor and Associate professor, University of Alabama at Birmingham, USA

1994-1999

Assistant Professor, University of Virginia, USA

1989-1994

Postdoctoral Fellow, Johns Hopkins University School of Medicine, USA

Research Direction

Research in Mei lab has focused on mechanisms of synapse formation, neurotransmission, and synaptic plasticity. Our goal is to contribute to a better understanding of these processes and development of potential therapeutic strategies for psychiatric disorders such as schizophrenia, autism, and depression and neurological disorders such as neuromuscular disorders and ALS.

Major Research Projects

1. The neuromuscular junction (NMJ) formation and disorders

Our daily activities – getting out of bed, walking, eating, drinking, and even sitting – require the proper function of the NMJ, a peripheral synapse between motoneurons and muscle fibers that is critical for accurate and rapid control of muscle contraction. This classic chemical synapse has served as an informative model of synapse structure and function. Although many synaptic components have been identified, how they are assembled to form the NMJ remains unclear. The NMJ formation requires agrin, a trophic factor from motoneurons and MuSK, a transmembrane tyrosine kinase in the muscle that can be activated by agrin; however, agrin does not interact with MuSK. We identified LRP4 as a receptor for agrin and revealed mechanisms how signals are transduced from agrin to MuSK by solving a crystal structure of an agrin-LRP4 complex. We have discovered antibodies against LRP4 and agrin in patients with myasthenia gravis and demonstrated that they are causal to myasthenia gravis. These antibodies are used as novel biomarkers for the diagnosis of myasthenia gravis. We demonstrated that rapsyn, a classic scaffold protein, undergoes liquid-liquid phase separation to form membraneless condensates for AChR clustering and NMJ formation. In addition, rapsyn possesses an E3 ligase activity that is required for NMJ formation. We have revealed novel pathways that are critical for the development, maintenance and regeneration of the NMJ.

Currently, we are studying how MuSK and rapsyn coordinate to promote the NMJ formation. Unlike anterograde signals that have been extensively studied, how muscles regulate motor neuron development and survival remains unclear, a topic that is currently explored in our lab. The NMJ is a tripartite synapse of motor nerve terminals, muscle fibers and terminal Schwann cells. We are identifying biomarkers of terminal Schwann cells to better understand their function in NMJ formation and function. Finally, we are exploring pathological mechanisms of muscular dystrophies including myasthenia gravis and ALS and their therapeutic interventions by improving NMJ functions.

2. Neuregulin 1 (NRG1) and ErbB4 signaling in dynamic control of GABAergic transmission

There are two main types of neurons: excitatory (also called projection or pyramidal) neurons that use glutamate as a neurotransmitter and inhibitory interneurons (INs) that release GABA, Comprising 15%–20% of total neurons in the brain, INs control the excitability of projection neurons. Via feedforward and feedback inhibition, interneurons increase the computational power of cortical networks and synchronize both local and distant cortical circuits that are key to oscillatory activity. Disruptions of GABA signaling have been implicated in brain disorders including autism, depression, intellectual disability, and schizophrenia. We have demonstrated that NRG1 and its receptor ErbB4 are critical to GABA activity in the brain. NRG1 is produced by pyramidal neurons in an activity-dependent manner. It binds to ErbB4 in INs to promote GABA release and thus suppresses the activity of pyramidal neurons. This homeostatic pathway is critical to many brain functions including working memory, attention and fear. Both NRG1 and ErbB4 are risk genes for major depression disorders and schizophrenia. Our research has provided insight into the pathophysiological mechanisms of devastating brain disorders and revealed novel targets for therapeutic intervention. Future research is to elucidate underlying mechanisms.

3. Pathological mechanisms of brain disorders

Many psychiatric disorders lack clear pathological hallmarks and thus are poorly understood in terms of pathophysiological mechanisms. With the advance in powerful genetic analysis, many risk genes have been identified for brain disorders. By studying mouse models of deficiency and/or de novo mutations, our studies reveal physiological functions of Erbin, TMEM108, NRG3, Caspr3, and Cullin 3 in neural development and neurotransmission and provide insight into pathophysiological mechanisms of schizophrenia, major depression, and autism.

Major Contributions

1. Discovered that LRP4 is a receptor of agrin that activates the transmembrane tyrosine kinase MuSK(Neuron, 2008; Genes & Dev.，2012)

2. Found anti-LRP4 and -agrin autoantibodies in patients with myasthenia gravis and showed in animal models that they are pathogenic, providing new leads for diagnosis and treatment of myasthenia gravis(Archive Neurol., 2012; PLoS One, 2014; J. Clin. Invest., 2013; Neuroscience, 2018; Neurology, 2021)

3. Revealed signaling mechanisms downstream of MuSK, including that rapsyn serves as an E3 ligase and undergoes liquid phase condensation, both events required for neuromuscular junction formation (Neuron, 2002, 2003, 2008, 2016; eLife, 2019；Neuron, 2021) , suggesting that rapsyn may act as a signaling protein, in addition to its classic scaffolding role.

4. Explored retrograde signaling pathways for muscles to regulate motoneuron differentiation (via muscle β-catenin and yet unidentified presynaptic protein that interacts with muscle LRP4(Nature Neuroscience, 2008; Neuron, 2012; eLife, 2015)

5. Discovered that the neuregulin 1 (NRG1)-ErbB4 pathway promotes GABAergic transmission to regulate many behaviors including working memory, fear, attention and pain (Neuron, 2000, 2007; PNAS, 2010a, 2010b; Neuron, 2013, 2014, 2018, 2022)

6. Revealed pathophysiological mechanisms of neuropsychiatric disorders such as depression, schizophrenia and autism by studying risk genes including erbin, cullin 3, Caspr3, TMEM108 and NRG3 (Nature Neurosci, 2013; PNAS, 2017, 2018; Neuron, 2020; JCI, 2021; Current Biol., 2021)

Representative Publications *：Co-first author; #：Co-corresponding author

Shen C*, Zhang B*, Lu Y*, Figueiredo D‎, Wu H, Arnab B, Xiong WC and Mei L. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. Journal of Clinical lnvestigation, 2013, 123: 5190-5202. DOI: 10.1172/JCI66039

Sun XD*^#, Li L*, Liu F, Huang ZH, Bean JC, Jiao HF, Barik A, Kim SM, Wu H, Shen C, Tian Y, Lin TW, Bates R, Sathyamurthy A, Chen YJ, Yin DM, Xiong L, Lin HP, Hu JX, Li BM, Gao TM, Xiong WC, Mei L^#. Lrp4 in astrocytes modulates glutamatergic transmission. Nature Neuroscience, 2016, 19: 1010-1018. DOI: 10.1038/nn.4326

Li L*, Cao Y*, Wu H, Ye X, Zhu Z, Xing G, Shen C, Barik A, Zhang B, Xie X, Zhi W, Gan L, Su H, Xiong WC, Mei L. Enzymatic activity of the scaffold protein rapsyn for synapse formation. Neuron, 2016, 92: 1007-1019. DOI: 10.1016/j.neuron.2016.10.023

Tan Z, Robinson H, Yin D, Liu Y, Liu F, Wang H, Lin TW, Xing G, Xiong WC, Mei L. Dynamic ErbB4 activity in hippocampal-prefrontal synchrony and top-down attention in rodents. Neuron, 2018, 98: 380-393. DOI: 10.1016/j.neuron.2018.03.018

Dong Z*, Chen W*, Chen C, Wang H, Cui W, Tan Z, Robinson H, Gao N, Luo B, Zhang L, Zhao K, Xiong WC and Mei L. CUL3 Deficiency Causes Social Deficits and Anxiety-like Behaviors by Impairing Excitation-Inhibition Balance through the Promotion of Cap-Dependent Translation. Neuron, 2020, 105: 475-490. DOI: 10.1016/j.neuron.2019.10.035 (Cover)

Chen WB*, Luo B*, Gao NN*, Li HW, Wang HS, Li L, Cui WP, Zhang L, Sun D, Liu F, Dong ZQ, Ren X, Zhang HS, Su HB, Xiong WC, and Mei L. Neddylation stabilizes Nav1.1 to maintain interneuron excitability and prevent seizures in murine epilepsy models. Journal of Clinical lnvestigation, 2021, 15: 131. DOI: 10.1172/JCI136956

Xing G, Jing H, Yu Z, Chen P, Wang H, Xiong WC, and Mei L. Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron, 2021, 109:1963-1978.DOI:10.1016/j.neuron.2021.04.021 (Cover)

Cui W, Gao N, Dong Z, Shen C, Zhang H, Luo B, Chen P, Comoletti D, Jing H, Wang H, Robinson H, Xiong WC, and Mei L. In-trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development. Current Biology, 2021, 31: 3330-3342.e7. DOI: 10.1016/j.cub.2021.05.045

Wang H, Chen W, Dong Z, Xing G, Cui W, Yao L, Zou WJ, Robinson HL, Bian Y, Liu Z, Zhao K, Luo B, Gao N, Zhang H, Ren X, Yu Z, Meixiong J, Xiong WC, and Mei L. A novel spinal neuron connection for heat sensation. Neuron, 2022, 110: 2315-2333. DOI: 10.1016/j.neuron.2022.04.021

Cao R, Chen P, Wang H, Jing H, Zhang H, Xing G, Luo B, Pan J, Yu Z, Xiong WC, Mei L. Intrafusal-fiber LRP4 for muscle spindle formation and maintenance in adult and aged animals. Nature Communications, 2023, 14: 744. DOI: 10.1038/s41467-023-36454-8

Full List of Publications Can Be Found here