Research Description
The human brain contains billions of neurons to receive and integrate a host of electrical and biochemical signals. Efficiency in communication among neurons is made possible by synapses, contacts formed between two neurons. We are interested in mechanisms of synapse formation, neurotransmission, and synaptic plasticity. Our studies contributes to identification of targets and development of potential therapeutic strategies for treating disorders whose pathogenesis involves abnormal synaptic structure and function. They include psychiatric disorders such as schizophrenia, autism, and depression and neurological disorders such as muscular dystrophy, spinal cord injury, and epilepsy.
NRG1, synaptic plasticity, schizophrenia and epilepsy
Neuregulin-1 (NRG1) is a family of polypeptides shown to play an important role in neural development (Mei and Xiong, 2008). It has been implicated in neuronal differentiation, migration, neurite outgrowth, and formation of excitatory synapses (Li et al., 2007). In addition, NRG1 and its receptor ErbB tyrosine kinases are also expressed in adult brain. ErbB receptors are concentrated at the postsynaptic density (PSD) of excitatory synapses, presumably via interaction with PDZ domain-containing proteins including PSD-95 and erbin, or lipid rafts (Huang et al., 2000; Huang et al., 2001; Ma et al., 2003). The synaptic localization of ErbB proteins suggests to us that NRG1s may regulate synaptic plasticity. Indeed we discovered in 2000 that NRG1 suppresses induction of long-term potentiation (LTP) in the hippocampal CA1 region, a cellular model of learning and memory, in collaboration with Dr. Mike Salter and colleagues (Huang et al., 2000). This finding, the first piece of evidence of NRG1’s role in synaptic plasticity, is exciting because recent genetic studies have associated the NRG1 gene with schizophrenia in diverse populations. Malfunction of NRG1 signaling at synapses may be a mechanism underlying this devastating disorder. NRG1 regulation of LTP requires ErbB4 (Pitcher et al., 2008), another susceptibility gene of schizophrenia.
γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian forebrain, essential to the proper function of the brain. GABAergic dysfunction is implicated in psychiatric disorders such as schizophrenia, anxiety, and depression and neurological disorders including Huntington’s chorea, Parkinson’s disease, and epilepsy. Remarkably, NRG1, via ErbB4 at GABAergic terminals, is able to regulate GABAergic transmission of the prefrontal cortex (Woo et al., 2007). These results identify a novel mechanism of NRG1 in regulation of neuronal activity in the brain and provide intriguing leads to pathological mechanisms of schizophrenia and epilepsy. Work in our lab now investigates whether NRG1 regulates brain activity at circuitry levels including pyramidal neuron firing, gamma waves and cognitive functions such as working memory.
NRG1/ErbB4 signaling is complex. NRG1 stimulation causes ErbB endocytosis that appears to be necessary for the activation of intracellular signaling (Yang et al., 2005; Liu et al., 2007). It is regulated by proteins interacting with ErbB kinases such as PSD-95 and erbin (Huang et al., 2000; Huang et al., 2003; Dai et al., 2006). Upon ErbB activation, several intracellular pathways become activated, which include Ras-Raf-Erk and PI3K (Si et al., 1996; Si et al., 1999). In non-canonical signaling, ErbB4 undergoes proteolytic cleavage to generate an intracellular domain that may regulate gene expression in the nucleus (Lee et al., 2002). Molecular mechanisms underlying NRG1-regulated synaptic plasticity are currently under investigation.
Representative publications on NRG1
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P. Dai, W.C. Xiong, and Lin Mei. Erbin inhibits RAF activation by disrupting the SUR-8-RAS-RAF complex. J. Biol. Chem. 281:927, 2006
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Y.Z. Huang, S.S. Won, D.W. Ali, Q. Wang, M. Tanowitz, Q.S. Du, W.C. Xiong, K.A. Pelkey, M.W. Salter, and Lin Mei. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 26:443-455, 2000
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Y.Z. Huang, Q. Wang, W.C. Xiong, L. Mei. Erbin is a protein concentrated at postsynaptic membranes that regulates surface expression of ErbB2. J. Biol. Chem. 276:19318-19326, 2001
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Y.Z. Huang, M. Zang, W.C. Xiong, Z. Luo, Lin Mei. Erbin suppresses the MAP kinase pathway. J. Biol. Chem. 278:1108-1114, 2003.
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H.-J. Lee, K.-M. Jung, Y.Z. Huang, L.B. Bennett, J.S. Lee, L. Mei, and T.-W. Kim. Presenilin-dependent gamma-secretase-like intramembrane cleavage of ErbB4. J. Biol. Chem. 277: 6318-6323, 2002
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B. Li, R.S. Woo, L. Mei, R. Malinow. The neuregulin1 receptor ErbB4 controls glutamatergic synapse maturation and plasticity. Neuron 54:583-597, 2007 (high-lighted in Preview by G. Fischbach, Neuron 54:495-497, 2007; in News and View by L.W. Role and D.A. Talmage Nature 448:263, 2007 and in Nature Review Neuroscience, 8:492, 2007).
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Y. Liu, Y. Tao, R.-S. Woo, W.C. Xiong, and Lin Mei. Stimulated ErbB4 internalization is necessary for neuregulin signaling in neurons. Biochem. Biophys. Rapid Comm. 354:505-510, 2007
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L. Ma,* Y.Z. Huang,* J.G. Valtschanoff, L.Y. Feng, B. Lu, W.C. Xiong, R.J. Weinberg, and L. Mei. Ligand dependent recruitment of the neuregulin-signaling complex into neuronal lipid rafts. J. Neurosci. 23:3164-3175, 2003. (highlighted in “This Week in The Journal”, J. Neurosci. 23(8):i, 2003) (*, equal contribution)
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L. Mei and W.C. Xiong. Neuregulin-1 signaling in neural development, synaptic plasticity and schizophrenia. Nature Rev. Neurosci. 9:437-452, 2008
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G.M. Pitcher, S. Beggs, R.-S. Woo, Lin Mei and M.W. Salter. ErbB4 is a suppressor of long-term potentiation in the adult hippocampus. NeuroReport 19:139-143, 2008
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J. Si, Z. Luo, and Lin Mei: Induction of acetylcholine receptor gene by ARIA requires activation of MAP kinase. J. Biol. Chem. 271:19752-19759, 1996.
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J. Si, Q. Wang, and Lin Mei: Essential roles of c-JUN and c-JUN NH2-terminal kinase (JNK) in neuregulin increased expression of acetylcholine receptor epsilon-subunit. J. Neurosci. 19:8498-8508, 1999
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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. Gao,* L. Mei.* Neuregulin-1 Enhances Depolarization-Induced GABA Release. Neuron 54:599-610, 2007 (high-lighted in Preview by G. Fischbach, Neuron 54:495-497, 2007; in News and View by L.W. Role and D.A. Talmage Nature 448:263, 2007 and in Nature Review Neurosci., 8:492, 2007). (*, equal contribution)
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X.L. Yang, Y.Z. Huang, W.C. Xiong, and Lin Mei. Neuregulin-induced Expression of the Acetylcholine Receptor Requires Endocytosis of ErbB Receptors. Mol. Cell. Neurosci. 28:335-346, 2005
Neuromuscular junction formation and muscular dystophy
One model we use to study synapse formation is the neuromuscular junction. Agrin, released from motoneurons, is essential for postsynaptic differentiation. It activates MuSK, a muscle-specific receptor tyrosine kinase. Mice lacking ether agrin or MuSK do not form the NMJ. However, how signal is transmitted from agrin to MuSK remained unclear. The extracellular domain of MuSK can bind to an activity on muscle surface that is involved in AChR clustering (Wang et al., 2008). Recently we found that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, functions as a co-receptor of agrin (Zhang et al., 2008). LRP4 is necessary for MuSK signalling and agrin-induced AChR clustering. Because mutations and/or autoimmunization of agrin signalling proteins may cause muscular dystrophies including myasthenia gravis and congenital myasthenic syndrome, these results suggest that LRP4 may be a potential culprit in these disorders.
We are making progress in understanding intracellular mechanisms of agrin signaling leading to AChR clustering. Agrin stimulation leads to MuSK recruitment into lipid rafts and endocytosis which appear to be necessary for AChR clustering in cultured muscle cells (Zhu et al., 2006; Zhu et al., 2007). A number of intracellular enzymes become activated in agrin-stimulated muscle cells, including Abl, casein kinase, geranylgeranyltransferase I (GGT I) (Luo et al., 2003), small G-proteins of the Rho family, and PAK1 (Luo et al., 2002). Their activity was shown to be necessary for receptor clustering in muscle cells and neuromuscular synapse formation in vitro or in vivo. Agrin/MuSK signaling could be regulated by proteins interacting with MuSK including LRP4 (Zhang et al., 2008), Dok-7, Dvl (Luo et al., 2002), or SHP2, a protein tyrosine phosphatase. However, muscle-specific mutation of the SHP2 gene does not appear to alter NMJ formation and maintenance (Dong et al., 2006).
Rapsyn is an AChR-interacting protein essential for NMJ formation. It seems to play a multi-facet role in AChR clustering. It could bridge AChRs to the cytoskeleton via the beta-catein/alpha-catenin complex (Zhang et al., 2007). On the other hand, it prevents the activation of Cdk5, a kinase downstream of the negative signal ACh to disperse AChR clusters (Chen et al., 2007). Using a proteomic approach to identify proteins that specifically associated with clustered surface AChR, we discovered a critical role of HSP90beta in AChR clustering by stabilizing rapsyn (Luo et al., 2008). Moreover, NMJ formation may be regulated at the levels of MuSK expression (Kim et al., 2003; Kim et al., 2005).
Neuromuscular junction formation requires interaction between motor neurons and muscle cells. Unfortunately, unlike antegrade signals, little is known about retrograde mechanisms from muscle to motor neurons. Intriguingly, our recent studies reveal an important role of muscle beta-catenin in the differentiation and/or function of motor nerves (Li et al., 2008). In the absence of muscle beta-catenin, AChR clusters were increased in size and distributed in a wider region in mutant mice, in agreement with in vitro studies (Zhang et al., 2007). Remarkably, mutant mice exhibit morphological deficits of motor nerve terminals, impaired neuromuscular transmission, and compromised plasticity and calcium sensitivity of neurotransmitter release. These observations demonstrate that muscle beta-catenin play a role in the development of both pre- and post-synaptic membranes. It is plausible that beta-catenin-dependent transcription is necessary for expression of a necessary retrograde signal protein.
Representative publications on NMJ formation
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F. Chen*, L. Qian*, Z.-H. Yang, Y. Huang, S.T. Ngo, N.-J. Ruan, J. Wang, C. Schneider, P.G. Noakes, Y.-Q. Ding, Lin Mei, Z.-G. Luo. Rapsyn interaction with calpain stabilizes AChR clusters at the neuromuscular junction. Neuron 55: 247-260, 2007 (*, equal contribution)
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X. P. Dong, X.-M. Li, T.-M. Gao, G.-S. Feng, W.C. Xiong, L. Mei. SHP2 is dispensable for neuromuscular junction formation and maintenance. NeuroSignals, 15:53-62, 2006
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C.-H. Kim, W.C. Xiong, L. Mei. Regulation of MuSK expression by a novel signaling pathway. J. Biol. Chem. 278:38522-38527, 2003
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C.-H. Kim, W.C. Xiong, L. Mei. Inhibition of MuSK expression by CREB interacting with a CRE-like element and MyoD. Mol. Cell. Biol. 25:5329-5338, 2005
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X.-M. Li,* X.-P. Dong,* S.W. Luo, B. Zhang, D.H. Lee, A.K.L. Ting, H. Neiswender, C.H. Kim, E. Carpenter-Hyladn, T.M. Gao, W.C. Xiong, L. Mei. Retrograde regulation of motoneuron differentiation by muscle β-catenin. Nature Neurosci. 11:262-268, 2008. (highlighted in News & Views by Fu et al., Nature Neurosci. 11:244, 2008). (*, equal contribution)
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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
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Z.G. Luo,* Q. Wang,* J.Z. Zhou, J. Wang, Z. Luo, M. Liu, X. He, A. Wynshaw-Boris, W.C. Xiong, B. Lu, Lin Mei. Regulation of AChR Clustering by Dishevelled Interacting with MuSK and PAK1. Neuron 35:489-505, 2002. (highlighted in Neurobiology Paper Alert, Curr. Opinion Neurobiol. 12:463-470, 2002). (*, equal contribution)
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Z.G. Luo, H.-S. Je, F. Yang, Z.-H. Yang, W.C. Xiong, B. Lu, L. Mei: Membrane Anchoring of Rho GTPases by Geranylgenanyltransferase is Required for Agrin-induced ACh Receptor Clustering. Neuron 40:703-717, 2003 (highlighted in “Faculty of 1000”, 2003)
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Q. Wang,* B. Zhang,* Y.E. Wang, W.C. Xiong, L. Mei. The Ig1/2 Domain of MuSK Binds to Muscle Surface and Is Involved in Acetylcholine Receptor Clustering. Neurosignals. 16:246-253, 2008. (*, equal contribution)
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B. Zhang,* S.W. Luo,* X.P. Dong,* Z. Luo, W.C. Xiong, L. Mei. beta-Catenin regulates AChR clustering in muscle cells through interaction with rapsyn. J. Neurosci. 27:3968-3973, 2007 (high-lighted in This Week in The Journal, J. Neurosci. 27:i, 2007 and in Nature Review Neuroscience, 8:324, 2007). (*, equal contribution)
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B. Zhang, S. Luo, Q. Wang, T. Suzuki, W.C. Xiong, Lin Mei. LRP4 serves as a co-receptor of agrin. Neuron 60:285-297, 2008 (highlighted in Nature 455:1153, 2008 and in Nature Review Neurosci., December, 2008)
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D. Zhu, W.-C. Xiong, and Lin Mei. Lipid Rafts Serve as a Signaling Platform for Nicotinic Acetylcholine Receptor Clustering. J. Neurosci. 26: 4841-4851, 2006
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D. Zhu, Z. Yang, Z. Luo, S. Luo, W.C. Xiong, Lin Mei. MuSK endocytosis in AChR clustering in response to agrin. J. Neurosci. 28:1688-1696, 2008. (highlighted in Faculty 1000)