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실험실 Bric, Biowave Vol. 22, No.6 (2020년 6월 9일) 소개

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댓글 0건 조회 927회 작성일 2020-06-10 17:54

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BioWave  Vol. 22 No. 6등록 2020.06.09 
대구경북과학기술원 시냅스 형성 및 구조 연구실고재원 교수
연구실 홈페이지
실험실 소개 
 
 Jaewon Ko is interested in how synapses form and function during development and in adulthood. His work focuses on (1) the role of synaptic cell-adhesion molecules in shaping synapse properties, (2) pre- and postsynaptic mechanisms of synaptic development, and (3) impairments in synapse formation and function in neuropsychiatric disorders. To address these questions, the Ko laboratory employs multiple, interdisciplinary approaches ranging from biochemical and biophysical studies to physiological and behavioral analyses of mutant mice deficient in key synaptic adhesion molecules and their associated proteins. The Ko laboratory is currently working on problems related to social cognitive processes at synaptic and circuit levels.
 
연구배경 
 
  Neurons communicate with each other through synaptic transmission at specialized intercellular junctions called 'synapses'. Synapses form not only during development, but also throughout life. Synapses transmit, process, and store information in the brain. During synaptic transmission, a presynaptic neuron releases a chemical neurotransmitter that is recognized by the postsynaptic neuron. Neurotransmitter release is triggered when an action potential opens voltage-gated calcium channels and calcium flows into the presynaptic nerve terminal. Released neurotransmitters elicit a postsynaptic response by binding to specific postsynaptic receptors. Work in Jaewon Ko's laboratory addresses three fundamental sets of questions about how synapses form and function: (1) how does a presynaptic nerve terminal form a synapse on a postsynaptic neuron in the first place; (2) how are the properties of the resulting synapses specified; and (3) how are synapses impaired in neuropsychiatric disorders? The overall goal is to describe the principal molecular mechanisms underlying these processes; that is, to identify the molecules involved, delineate their properties and structures, and understand their physiological functions. Two major research projects are ongoing in the laboratory.
 
연구분야 
 
1. Synapse formation and function by key synaptic cell-adhesion molecules

 At a synapse, pre- and postsynaptic compartments are linked by trans-synaptic cell-adhesion molecules that, in turn, are coupled to the presynaptic release machinery or postsynaptic receptors. Synaptic cell-adhesion molecules (CAMs) function in various stages of synaptogenesis - the process of synapse creation - encompassing synapse formation, maturation, refinement, plasticity, and elimination. We are currently focusing on a subset of the known synaptic CAMs, primarily LRRTMs, Slitrks, LAR-RPTPs, MDGAs and calsyntenins; however, their synaptic functions have only recently begun to come into focus. LRRTMs (leucine-rich repeat transmembrane proteins) and Slitrks (Slit and Trk-like family) contain leucine-rich repeats (LRRs) that function as protein-protein interaction domains (Figure 1) and govern the distinct types of synapse development and function (i.e., LRRTMs, Slitrk1, Slitrk2, Slitrk4 and Slitrk5 in excitatory synapses vs. Slitrk3 in inhibitory synapses). Intriguingly, LAR-RPTPs function in concert with Slitrks in an isoform-dependent manner. Calsyntenins, evolutionarily conserved postsynaptic CAMs, dictate inhibitory synapse development and function, partly in conjunction with presynaptic neurexins. Researchers in the Ko laboratory are interested in exploring the synaptic functions of a series of these synaptic CAMs in cultured neurons and transgenic mice.

Lab_intro

 

2. Synapse formation and function by synaptic cell adhesion-associated scaffolds

 For synaptic CAMs to exert biological effects in neurons, signals generated by their physical and chemical attachment must be intracellularly transduced to each compartment. Major scaffolding proteins have been identified and shown to interact with synaptic CAMs; for example, the important post-synaptic density protein PSD-95 interacts with neuroligins, LRRTMs, netrin-G ligands, and SALMs (synaptic cell adhesion-like molecules). However, it remains unclear how signals generated by the unique pairings of synaptic adhesion molecules affect intracellular signal transduction pathways; clarifying this issue is crucial for understanding how synaptic CAMs act independently and collaboratively to maintain/regulate the structure and function of synapses. The Ko laboratory is interested in discovering novel scaffolds that interact with key synaptic CAMs and deciphering the detailed flow of intracellular signals in both pre- and postsynaptic neurons. On a larger scale, a major challenge in the field is to understand how these synaptic CAMs shape neural circuits and collaborate with other trans-synaptic CAMs. An even more important and broader question is how synapses form in the first place and what additional molecules shape their properties. Ko laboratory researchers have recently made the interesting observation that members of the glycosylphatidylinositol (GPI)-anchored protein family (MDGAs) directly interact with and alter the cell-adhesion properties of neuroligin-2 to regulate inhibitory synapse development and function. In general, how neural circuits are established and how key synaptic CAMs contribute to their formation are among the major questions of modern neuroscience. The molecular components involved are only now beginning to be identified; undoubtedly many additional synaptic CAMs will ultimately be implicated. Given the complexity of synaptic connectivity, a combinatorial code?possibly one based on rather simple principles?may apply. Unraveling this code, which will almost certainly involve a major role for key synaptic CAMs as central trans-synaptic organizers, would significantly advance the molecular neuroscience field. Addressing these questions is the major theme of the Ko laboratory’s current research.

 

 
연구성과 
 

Publications (2017년 이후)

Han KA, Lee HY, Lim D, Shin J, Yoon TH, Liu X, Um JW, Choi SY and Ko J (2020). "Protein tyrosine phosphatase delta is not essential for synapse maintenance or synaptic transmission at hippocampal synapses" Mol Brain In Press

Han KA, Lee HY, Lim D, Shin J, Yoon TH, Lee C, Rhee JS, Liu X, Um JW, Choi SY* and Ko J* (2020). "PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses" iScience In Press *Corresponding authors

Kim H, Kim D, Kim J, Lee HY, Park D, Kang H, Matsuda K, Sterky FH, Yuzaki M, Kim JY, Choi SY, Ko J* and Um JW* (2020). "Calsyntenin-3 directly interacts with both alpha- and beta-neurexins to regulate excitatory synaptic innervation in specific Schaffer collateral neural circuits" J Biol Chem In Press *Corresponding authors

Karki S, Shkumatov AV, Bae S, Kim H, Ko J and Kajander T (2020). "Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ" Sci Rep In Press. Abstract

Kim S, Kim H, Park D, Kim J, Hong J, Kim J, Jung H, Kim D, Cheong E, Ko J* and Um JW* (2020). "Loss of IQSEC3 Disrupts GABAergic Synapse Maintenance and Decreases Somatostatin Expression in the Hippocampus" Cell Rep 30(6): 1995-2005. E5 *Corresponding authors. Abstract

Sung G, Lee SY, Kang MG, Kim KL, An J, Sim J, Kim S, Kim S, Ko J, Rhee HW, Park KM and Kim K (2020). "Supra-blot: an accurate and reliable assay for detecting target proteins with a synthetic host molecule-enzyme hybrid" Chem Comm 56(10): 1549-1552. Abstract

Kim H, Jung H, Jung H, Kwon SK, Ko J and Um JW (2020)."The small GTPase ARF6 regulates GABAergic synapse development" Mol Brain 13(1): 2. Abstract

Han KA, Kim J, Kim H, Kim D, Lim D, Ko J and Um JW (2019)."Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions" Sci Rep 9(1): 17094. Abstract

Han KA, Um JW and Ko J (2019). "Intracellular Protein Complexes Involved in Synapse Assembly in Presynaptic Neurons" Adv Protein Chem Struct Biol : Intracellular Signaling Proteins 116: 347-373 (an invited book chapter). Abstract

Zhang C and Ko J (2018). "Editorial: Synaptic Assembly and Neural Circuit Development" Front Synaptic Neurosci 10: 30. doi: 10.3389/fsyn.2018.00030. eCollection 2018 (Editorial article). Abstract

Han KA, Ko JS, Pramanik G, Kim JY, Tabuchi K, Um JW and Ko J (2018). "PTPσ drives excitatory presynaptic assembly via various extracellular and intracellular mechanisms" J Neurosci 38(30): 6700-6721. Abstract
[Selected as a Featured Article and highlighted in "This Week in The Journal"]

Li Y, Kim R, Cho YS, Song WS, Kim D, Kim K, Rho JD, Chung C, Park H, Yang E, Kim SJ, Ko J, Kim H, Kim MH, Bae YC and Kim E (2018). "Lrfn2-mutant mice display suppressed synaptic plasticity and inhibitory synapse development and abnormal social communication and startle response" J Neurosci 38(26): 5872-5887. Abstract

Park D, Bae S, Yoon TH and Ko J (2018). "Molecular Mechanisms of Synaptic Specificity: Spotlight on Hippocampal and Cerebellar Synapse Organizers" Mol Cells 41(5): 373-380 (an invited minireview). Abstract

Ko J* and Kim E (2018). "Special Issue on Synapse Assembly, Neural Circuit Development, and Brain Disorders" Exp Mol Med 50(4):17 (Editorial article) *Corresponding author. Abstract

Won SY, Kim CY, Kim D, Ko J, Um JW, Lee SB, Buck M, Kim E, Heo WD, Lee JO and Kim HM (2017). "LAR-RPTP Clustering is Modulated by Competitive Binding Between Synaptic Adhesion Partners and Heparan Sulfate" Front Mol Neurosci 10:327. Abstract

Um JW and Ko J (2017). "Neural Glycosylphosphatidylinositol-Anchored Proteins in Synaptic Specification" Trends Cell Biol 27(12), 931-945 (an invited review). Abstract, 한빛사논문

Ko J (2017). "Neuroanatomical substrates of rodent social behavior: The medial prefrontal cortex and its projection patterns" Front Neural Circuits 11:41 (an invited review). Abstract

Kim JA, Kim D, Won SY, Han KA, Park D, Cho E, Yun N, An HJ, Um JW, Kim E, Lee JO, Ko J*, and Kim HM* (2017). "Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex" Neuron 94(6), 1121-1131 *Corresponding authors. Abstract, 한빛사논문
[Featured as an "Issue Highlight"]
[Highlighted in a 'Preview']

Takahashi H, Matsuda K, Tabuchi K and Ko J (2017). "Central synapse, neural circuit, and brain function" Neurosci Res 116, 1-2 (Editorial article). Abstract

Roh JD, Choi SY, Cho YS, Choi TY, Park JS, Curtforth T, Chung W, Park H, Lee D, Kim MH, Lee Y, Lee D, Rhee JS, Kim H, Ko J, Choi SY, Bae YC, Shen K, Kim E and Han K (2017). "Increased excitatory synaptic transmission of dentate granule neurons in mice lacking PSD-95-interacting adhesion molecule Neph2/Kirrel3 during the early postnatal period" Front Mol Neurosci 10:81. doi: 10.3389/fnmol.2017.00081. Abstract

 
   
 
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 Graduate students: 윤택한, 김승준, 서나영
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