PMID- 37120096
OWN - NLM
STAT- MEDLINE
DCOM- 20230607
LR  - 20231115
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 182
DP  - 2023 Jun 15
TI  - FMRP phosphorylation and interactions with Cdh1 regulate association with 
      dendritic RNA granules and MEF2-triggered synapse elimination.
PG  - 106136
LID - S0969-9961(23)00150-X [pii]
LID - 10.1016/j.nbd.2023.106136 [doi]
AB  - Fragile X Messenger Ribonucleoprotein (FMRP) is necessary for 
      experience-dependent, developmental synapse elimination and the loss of this 
      process may underlie the excess dendritic spines and hyperconnectivity of 
      cortical neurons in Fragile X Syndrome, a common inherited form of intellectual 
      disability and autism. Little is known of the signaling pathways that regulate 
      synapse elimination and if or how FMRP is regulated during this process. We have 
      characterized a model of synapse elimination in CA1 neurons of organotypic 
      hippocampal slice cultures that is induced by expression of the active 
      transcription factor Myocyte Enhancer Factor 2 (MEF2) and relies on postsynaptic 
      FMRP. MEF2-induced synapse elimination is deficient in Fmr1 KO CA1 neurons, and 
      is rescued by acute (24 h), postsynaptic and cell autonomous reexpression of FMRP 
      in CA1 neurons. FMRP is an RNA binding protein that suppresses mRNA translation. 
      Derepression is induced by posttranslational mechanisms downstream of 
      metabotropic glutamate receptor signaling. Dephosphorylation of FMRP at S499 
      triggers ubiquitination and degradation of FMRP which then relieves translation 
      suppression and promotes synthesis of proteins encoded by target mRNAs. Whether 
      this mechanism functions in synapse elimination is not known. Here we demonstrate 
      that phosphorylation and dephosphorylation of FMRP at S499 are both necessary for 
      synapse elimination as well as interaction of FMRP with its E3 ligase for FMRP, 
      APC/Cdh1. Using a bimolecular ubiquitin-mediated fluorescence complementation 
      (UbFC) assay, we demonstrate that MEF2 promotes ubiquitination of FMRP in CA1 
      neurons that relies on activity and interaction with APC/Cdh1. Our results 
      suggest a model where MEF2 regulates posttranslational modifications of FMRP via 
      APC/Cdh1 to regulate translation of proteins necessary for synapse elimination.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Wilkerson, Julia R
AU  - Wilkerson JR
AD  - Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical 
      Center, Dallas, TX, USA.
FAU - Ifrim, Marius F
AU  - Ifrim MF
AD  - Department of Cell and Developmental Biology, State University of New York, 
      Upstate Medical University, Syracuse, NY 13210, USA; Department of Cell Biology, 
      Emory University School of Medicine, Atlanta, GA 30322, USA.
FAU - Valdez-Sinon, Arielle N
AU  - Valdez-Sinon AN
AD  - Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Hahn, Patricia
AU  - Hahn P
AD  - Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical 
      Center, Dallas, TX, USA.
FAU - Bowles, Jacob E
AU  - Bowles JE
AD  - Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical 
      Center, Dallas, TX, USA.
FAU - Molinaro, Gemma
AU  - Molinaro G
AD  - Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical 
      Center, Dallas, TX, USA.
FAU - Janusz-Kaminska, Aleksandra
AU  - Janusz-Kaminska A
AD  - Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 
      30322, USA.
FAU - Bassell, Gary J
AU  - Bassell GJ
AD  - Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 
      30322, USA. Electronic address: gbassel@emory.edu.
FAU - Huber, Kimberly M
AU  - Huber KM
AD  - Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical 
      Center, Dallas, TX, USA. Electronic address: Kimberly.Huber@UTSouthwestern.edu.
LA  - eng
GR  - R01 HD052731/HD/NICHD NIH HHS/United States
GR  - R01 MH109026/MH/NIMH NIH HHS/United States
GR  - T32 GM008169/GM/NIGMS NIH HHS/United States
GR  - T32 GM142617/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230428
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (MEF2 Transcription Factors)
RN  - 0 (messenger ribonucleoprotein)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
RN  - 0 (Fmr1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - MEF2 Transcription Factors/metabolism
MH  - *Fragile X Mental Retardation Protein/genetics/metabolism
MH  - Phosphorylation/genetics
MH  - Synapses/metabolism
MH  - *Fragile X Syndrome/genetics
MH  - Mice, Knockout
PMC - PMC10370323
MID - NIHMS1914714
OTO - NOTNLM
OT  - Cdh1
OT  - FMRP
OT  - Hippocampal CA1
OT  - MEF2
OT  - Synapse elimination
EDAT- 2023/04/30 00:42
MHDA- 2023/06/07 06:42
PMCR- 2023/07/26
CRDT- 2023/04/29 19:29
PHST- 2023/02/20 00:00 [received]
PHST- 2023/04/12 00:00 [revised]
PHST- 2023/04/24 00:00 [accepted]
PHST- 2023/06/07 06:42 [medline]
PHST- 2023/04/30 00:42 [pubmed]
PHST- 2023/04/29 19:29 [entrez]
PHST- 2023/07/26 00:00 [pmc-release]
AID - S0969-9961(23)00150-X [pii]
AID - 10.1016/j.nbd.2023.106136 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2023 Jun 15;182:106136. doi: 10.1016/j.nbd.2023.106136. Epub 2023 
      Apr 28.