PMID- 29934346
OWN - NLM
STAT- MEDLINE
DCOM- 20191028
LR  - 20200306
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 38
IP  - 30
DP  - 2018 Jul 25
TI  - PTPsigma Drives Excitatory Presynaptic Assembly via Various Extracellular and 
      Intracellular Mechanisms.
PG  - 6700-6721
LID - 10.1523/JNEUROSCI.0672-18.2018 [doi]
AB  - Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are 
      hub proteins that organize excitatory and inhibitory synapse development through 
      binding to various extracellular ligands. Here, we report that knockdown (KD) of 
      the LAR-RPTP family member PTPsigma reduced excitatory synapse number and 
      transmission in cultured rat hippocampal neurons, whereas KD of PTPdelta produced 
      comparable decreases at inhibitory synapses, in both cases without altering 
      expression levels of interacting proteins. An extensive series of rescue 
      experiments revealed that extracellular interactions of PTPsigma with Slitrks are 
      important for excitatory synapse development. These experiments further showed 
      that the intracellular D2 domain of PTPsigma is required for induction of 
      heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of 
      LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic 
      machinery assembly. Consistent with this, double-KD of liprin-alpha2 and -alpha3 or KD of 
      PTPsigma substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, 
      PTPsigma-mediated heterologous synapse formation activity. We propose a 
      synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized 
      retrograde signaling cascades, in which both extracellular and intracellular 
      mechanisms are critical in orchestrating distinct synapse types.SIGNIFICANCE 
      STATEMENT In this study, we sought to test the unproven hypothesis that PTPsigma and 
      PTPdelta are required for excitatory and inhibitory synapse formation/transmission, 
      respectively, in cultured hippocampal neurons, using knockdown-based 
      loss-of-function analyses. We further performed extensive structure-function 
      analyses, focusing on PTPsigma-mediated actions, to address the mechanisms of 
      presynaptic assembly at excitatory synaptic sites. Using interdisciplinary 
      approaches, we systematically applied a varied set of PTPsigma deletion variants, 
      point mutants, and splice variants to demonstrate that both extracellular and 
      intracellular mechanisms are involved in organizing presynaptic assembly. 
      Strikingly, extracellular interactions of PTPsigma with heparan sulfates and Slitrks, 
      intracellular interactions of PTPsigma with liprin-alpha and its associated proteins 
      through the D2 domain, as well as distinct substrates are all critical.
CI  - Copyright (c) 2018 the authors 0270-6474/18/386700-22$15.00/0.
FAU - Han, Kyung Ah
AU  - Han KA
AUID- ORCID: 0000-0001-6353-1042
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology, Daegu 42988, Korea.
FAU - Ko, Ji Seung
AU  - Ko JS
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology, Daegu 42988, Korea.
FAU - Pramanik, Gopal
AU  - Pramanik G
AUID- ORCID: 0000-0002-9117-4887
AD  - Department of Molecular and Cellular Physiology, Shinshu University School of 
      Medicine, Matsumoto 390-8621, Japan.
FAU - Kim, Jin Young
AU  - Kim JY
AUID- ORCID: 0000-0002-0656-1269
AD  - Biomedical Omics Group, Korea Basic Science Institute, Cheongju, Chungbuk 28119, 
      Korea, and.
FAU - Tabuchi, Katsuhiko
AU  - Tabuchi K
AUID- ORCID: 0000-0002-1673-4637
AD  - Department of Molecular and Cellular Physiology, Shinshu University School of 
      Medicine, Matsumoto 390-8621, Japan.
AD  - Department of Biological Sciences for Intractable Neurological Diseases, 
      Institute for Biomedical Sciences Interdisciplinary Cluster for Cutting Edge 
      Research, Shinshu University, Matsumoto 390-8621, Japan.
FAU - Um, Ji Won
AU  - Um JW
AUID- ORCID: 0000-0002-9355-7726
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology, Daegu 42988, Korea.
FAU - Ko, Jaewon
AU  - Ko J
AUID- ORCID: 0000-0001-9184-1574
AD  - Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science 
      and Technology, Daegu 42988, Korea, jaewonko@dgist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180622
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 2)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Neurogenesis/*physiology
MH  - Neurons/physiology
MH  - Rats
MH  - Receptor-Like Protein Tyrosine Phosphatases, Class 2/*metabolism
MH  - Signal Transduction/physiology
MH  - Synapses/*physiology
MH  - Synaptic Transmission/*physiology
PMC - PMC6705959
OTO - NOTNLM
OT  - LAR-RPTPs
OT  - PTPsigma
OT  - presynaptic assembly
OT  - protein-protein interaction
OT  - synaptic adhesion molecule
EDAT- 2018/06/24 06:00
MHDA- 2019/10/29 06:00
PMCR- 2019/01/25
CRDT- 2018/06/24 06:00
PHST- 2018/03/13 00:00 [received]
PHST- 2018/05/22 00:00 [revised]
PHST- 2018/06/14 00:00 [accepted]
PHST- 2018/06/24 06:00 [pubmed]
PHST- 2019/10/29 06:00 [medline]
PHST- 2018/06/24 06:00 [entrez]
PHST- 2019/01/25 00:00 [pmc-release]
AID - JNEUROSCI.0672-18.2018 [pii]
AID - 0672-18 [pii]
AID - 10.1523/JNEUROSCI.0672-18.2018 [doi]
PST - ppublish
SO  - J Neurosci. 2018 Jul 25;38(30):6700-6721. doi: 10.1523/JNEUROSCI.0672-18.2018. 
      Epub 2018 Jun 22.