- Novel signaling mechanisms that regulate synaptic and cognitive functions
- Synaptic dysfunction in brain disorders
- Intracellular transport in neuron
Dr. Lai Kwok On received his Bachelor degree of Biochemistry from the University of Hong Kong. He then pursued postgraduate studies at the Hong Kong University of Science and Technology (HKUST). With the award of the Croucher Foundation Fellowship, he performed postdoctoral research at UCLA in the United States.
Using a combination of molecular, biochemical and cellular approaches, Dr. Lai aims to elucidate the signal transduction mechanisms that underlie the development and functioning of neuronal synapses in the brain. This would lead us to a better understanding of the cellular and molecular mechanisms underlying long-term memory, and the pathophysiology of various neurodevelopmental disorders in the brain.
Our brains are remarkably “plastic”, an essential feature that enables adaptation to changes in the environment. This plastic nature of the brain is attributed to the ability of neurons to change their synaptic connectivity by experience. Synaptic plasticity involves structural modification of synapses, and depends on multiple cellular processes such as re-organization of cytoskeleton, local dendritic protein synthesis near synapses, and gene transcription in the nucleus.
Dendritic spines are specialized protrusions on dendrites where most excitatory synapses are present. Spines are highly dynamic, and their development and morphology are tightly regulated by neuronal activity. I am interested in understanding the molecular mechanisms by which neuronal activity controls dendritic spine development and plasticity. Using a combination of molecular, biochemical and cellular approaches, I have been focusing on how protein phosphorylation by kinases, such as the receptor tyrosine kinase TrkB and the serine/threonine kinase Cdk5, is involved in activity-dependent changes of spine morphogenesis. Whereas protein phosphorylation is arguably the most-studied form of post-translational modification of proteins in signal transduction, emerging studies have uncovered many other ways by which proteins are modified. However, the physiological function of most of these post-translational modifications in neuron remains elusive. One of my research focuses is to delineate the regulatory role of these post-translational modifications on synaptic proteins.
Another area of research in my laboratory is to study local dendritic protein synthesis in the regulation of dendritic spine development. There are subsets of mRNAs that are not only present in the neuronal cell body but can also be actively transported to dendrites via the formation of ribonucleoprotein (RNP) particles and granules. Local dendritic protein synthesis is essential for the persistent changes in synaptic efficacy during memory formation, yet very few dendritic mRNA transcripts and their encoded proteins have been directly linked to structural modification of synapses. With the advances in microarray analysis and deep sequencing, many dendritically localized mRNAs have been recently identified in neurons. Interestingly, the functions of many of these encoded proteins, including those with genetic variations that are associated with different brain disorders, have not been characterized in neuron. These recent transcriptomic studies should therefore represent important resources to identify novel proteins and signaling pathways that modulate spine morphogenesis. Using in situ hybridization of fixed neurons and time-lapse imaging of RNAs in living neurons, I aim to examine the trafficking and localization of these mRNAs in neuronal dendrites, and to explore their function and underlying mechanisms in the regulation of synaptic and cognitive function.
- mRNA trafficking and localization in neuronal dendrites
- Novel regulatory mechanism of dendritic spine morphogenesis and the link to neurological diseases
- Zhao J#, Fok AHK#, Fan R, Kwan PYi, Chan HL, Lo LHY, Chan YS, Yung WH, Huang JD, Lai CSW*, Lai KO* (2020) Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory. eLife. doi:10.7554/eLife.53456.
- Lin L, Lyu Q#, Kwan PY, Zhao J, Fan R, Chai A, Lai CSW, Chan YS, Shen X#, Lai KO* (2020) The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors. PLoS Genet. 16(1):e1008587. doi:10.1371/journal.pgen.1008587.
- Shen X, Yeung HT, Lai KO* (2018) Application of Human-Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders. Dev. Neurobiol. doi: 10.1002/dneu.22644 (invited review).
- Huang H, Lin X, Liang Z, Zhao T, Du S, Loy MMT, Lai KO, Fu AKY, Ip NY (2017) Cdk5-dependent phosphorylation of liprinα1 mediates neuronal activity-dependent synapse development. Proc. Natl. Acad. Sci. U.S.A. 114(33):E6992-E7001.
- Lin LF, Lo LHY, Lyu, Q, Lai KO* (2017) Determination of dendritic spine morphology by the striatin scaffold protein STRN4 through interaction with the phosphatase PP2A. J. Biol. Chem. 292: 9451-9464
- Liang Z, Zhan Y, Wong CC, Yates JR 3rd, Plattner F, Lai KO, Ip NY (2016) The pseudokinase CaMKv is required for the activity-dependent maintenance of dendritic spines. Nat. Commun. 7:13282. doi: 10.1038/ncomms13282.
- Tong BC, Lee CS, Cheng WH, Lai KO, Foskett JK, Cheung KH (2016) Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci. Signal. 9: ra89. doi: 10.1126/scisignal.aaf1371.
- Lai KO*, Jordan BA, Ma XM, Srivastava DP, Tolias KF (2016) Molecular Mechanisms of Dendritic Spine Development and Plasticity. Neural Plast. 2016: 2078121 (invited editorial).
- Lai KO*, Liang Z, Fei E, Huang H, Ip NY* (2015) Cyclin-dependent kinase 5 (Cdk5)-dependent phosphorylation of p70 ribosomal S6 kinase 1 (S6K) is required for dendritic spine morphogenesis. J. Biol. Chem. 290: 14637-14646.
- Lai KO, Ip NY (2013) Structural plasticity of dendritic spines: The underlying mechanisms and its dysregulation in brain disorders. Biochim. et Biophys. Acta.1832: 2257-2263.
- Lai KO, Wong ASL, Cheung MC, Xu P, Liang Z, Lok KC, Xie H, Palko ME, Yung WH, Tessarollo L, Cheung ZH, Ip NY (2012) Serine phosphorylation of TrkB by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat. Neurosci. 15: 1506-1515. [The study has been highlighted in the News and Views of Nature Neuroscience (http://www.nature.com/neuro/journal/v15/n11/full/nn1112-1474.html), Editor’s choice of Science Signaling (http://stke.sciencemag.org/cgi/content/abstract/sigtrans;5/249/ec287) and Faculty 1000 Biology (http://f1000.com/prime/717968360)].
- Fu AK, Hung KW, Fu WY, Shen C, Chen Y, Xia J, Lai KO, Ip NY (2011) APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat. Neurosci. 14: 181-189.
- Lai KO, Ip NY (2009) Synapse formation and plasticity: roles of ephrin/Eph receptor signaling. Curr. Opin. Neurobiol. 19: 275-283.
- Lai KO, Ip NY (2009) Recent advances in understanding the roles of Cdk5 in neuronal plasticity. Biochim. et Biophys. Acta.1792: 741-745.
- Lai KO, Wang D, Martin KC (2009) Signaling between synapse and nucleus during synaptic plasticity, in Intracellular Traffic and Neurodegenerative Disorders, Research and Perspectives in Alzheimer’s Disease, eds St. George Hyslop P. et al. Springer-Verlag Berlin Heidelberg, p. 71-86.
- Lai KO, Zhao Y, Ch’ng TH, Martin KC (2008) Importin-mediated retrograde transport of CREB2/ATF4 from distal processes to the nucleus in neurons. Proc. Natl. Acad. Sci. U.S.A. 44: 17175-17180. [The study has been highlighted by the Faculty 1000 Biology (http://f1000biology.com/article/id/1138064/evaluation)]
- Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AKY, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat. Neurosci. 10: 67-76.
- Lai KO, Chen Y, Po HM, Lok KC, Gong K, Ip NY (2004) Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. J. Biol. Chem. 279: 13383-13392.
- Lai KO, Ip NY (2003) Central synapse and neuromuscular junction: same players, different roles. Trends Genet. 19: 395-402.
- Xu Z#, Lai KO#, Zhou HM, Lin SC, Ip NY (2003) Ephrin-B1 reverse signaling activates JNK through a novel mechanism that is independent of tyrosine phosphorylation. J. Biol. Chem. 278: 24767-24775. (#equal contribution to the work)
- Lai KO, Ip FC, Cheung J, Fu AK, Ip NY (2001) Expression of Eph receptors in skeletal muscle and their localization at the neuromuscular junction. Mol. Cell. Neurosci. 17: 1034-1047.
- Lai KO, Fu WY, Ip FC, Ip NY (1998) Cloning and Expression of a Novel Neurotrophin, NT-7, from Carp. Mol. Cell. Neurosci. 11: 64-76.
- Health and Medical Research Fund (HMRF) 2019-2022 (Principal Investigator)
- RGC - General Research Fund 2018-21 (Principal Investigator)
- RGC - General Research Fund 2016-19 (Principal Investigator)
- RGC - Early Career Scheme 2015-18 (Principal Investigator)
- RGC - General Research Fund 2014-17 (Principal Investigator)
- RGC - General Research Fund 2010-13 (Principal Investigator)
- RGC - General Research Fund 2009-12 (Principal Investigator)
- Liu Po Shan/Dr Vincent Liu Endowment Fund for Motor Neuron Disease 2018-20 (Principal Investigator)
- Area of Excellence 2017-25 (Co-Investigator)
- Theme-based Research Scheme 2018-23 (Co-principal Investigator)
- Health and Medical Research Fund (HMRF) 2014-2016 (Co-Investigator)
- Co-Chair; SKL Neuroscience Symposium and Annual Scientific Conference of the Hong Kong Society of Neurosciences 2016
- Associate Chair; Gordon Research Seminar (Molecular and Cellular Neurobiology) 2014
- Croucher Foundation Fellowship 2003-2005
- Croucher Foundation Scholarship 2000-2001
- Sir Edward Youde Memorial Fellowship 1993-1994
- Sir Edward Youde Memorial Scholarship 1992-1993
- Scientific Reports
- Frontiers in Molecular Neuroscience
- Neural Plasticity (Special Issue: Molecular Mechanisms of Dendritic Spine Development and Plasticity)
- Lianfeng LIN (Postdoctoral fellow)
- Leonard CHEUNG (Technical Officer)
- Ruolin FAN (Ph.D Student)
- Junjun ZHAO (Ph.D Student)
- Louisa Hoi Ying LO (Ph.D Student)%
Last updated: February 4, 2020