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LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding

 Ji Won Um  ;  Tae-Yong Choi  ;  Hyeyeon Kang  ;  Yi Sul Cho  ;  Gayoung Choii  ;  Pavel Uvarov  ;  Dongseok Park  ;  Daun Jeong  ;  Sangmin Jeon  ;  Dongmin Lee  ;  Hyun Kim  ;  Seung-Hee Lee  ;  Yong-Chul Bae  ;  Se-Young Choi  ;  Matti S. Airaksinen  ;  Jaewon Ko 
 CELL REPORTS, Vol.14(4) : 808-822, 2016 
Journal Title
Issue Date
Alternative Splicing* ; Animals ; CA1 Region, Hippocampal/cytology ; CA1 Region, Hippocampal/growth & development ; CA1 Region, Hippocampal/metabolism ; Cell Adhesion Molecules, Neuronal/genetics ; Cell Adhesion Molecules, Neuronal/metabolism* ; Cells, Cultured ; Dentate Gyrus/cytology ; Dentate Gyrus/growth & development ; Dentate Gyrus/metabolism ; Excitatory Postsynaptic Potentials* ; HEK293 Cells ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurogenesis ; Protein Transport ; Pyramidal Cells/metabolism ; Pyramidal Cells/physiology ; Rats ; Receptors, AMPA/metabolism ; Synapses/metabolism ; Synapses/physiology
LRRTM3 ; LRRTM4 ; alternative splicing ; dentate gyrus ; excitatory synapse development ; glypican ; neurexin
The four members of the LRRTM family (LRRTM1-4) are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG) granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Um, Ji Won(엄지원)
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