Cargando…

FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission

Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients a...

Descripción completa

Detalles Bibliográficos
Autores principales: Leahy, Shannon N., Song, Chunzhu, Vita, Dominic J., Broadie, Kendal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879533/
https://www.ncbi.nlm.nih.gov/pubmed/36701299
http://dx.doi.org/10.1371/journal.pbio.3001969
_version_ 1784878712184897536
author Leahy, Shannon N.
Song, Chunzhu
Vita, Dominic J.
Broadie, Kendal
author_facet Leahy, Shannon N.
Song, Chunzhu
Vita, Dominic J.
Broadie, Kendal
author_sort Leahy, Shannon N.
collection PubMed
description Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength.
format Online
Article
Text
id pubmed-9879533
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-98795332023-01-27 FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission Leahy, Shannon N. Song, Chunzhu Vita, Dominic J. Broadie, Kendal PLoS Biol Research Article Noonan syndrome (NS) and NS with multiple lentigines (NSML) cognitive dysfunction are linked to SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) gain-of-function (GoF) and loss-of-function (LoF), respectively. In Drosophila disease models, we find both SHP2 mutations from human patients and corkscrew (csw) homolog LoF/GoF elevate glutamatergic transmission. Cell-targeted RNAi and neurotransmitter release analyses reveal a presynaptic requirement. Consistently, all mutants exhibit reduced synaptic depression during high-frequency stimulation. Both LoF and GoF mutants also show impaired synaptic plasticity, including reduced facilitation, augmentation, and post-tetanic potentiation. NS/NSML diseases are characterized by elevated MAPK/ERK signaling, and drugs suppressing this signaling restore normal neurotransmission in mutants. Fragile X syndrome (FXS) is likewise characterized by elevated MAPK/ERK signaling. Fragile X Mental Retardation Protein (FMRP) binds csw mRNA and neuronal Csw protein is elevated in Drosophila fragile X mental retardation 1 (dfmr1) nulls. Moreover, phosphorylated ERK (pERK) is increased in dfmr1 and csw null presynaptic boutons. We find presynaptic pERK activation in response to stimulation is reduced in dfmr1 and csw nulls. Trans-heterozygous csw/+; dfmr1/+ recapitulate elevated presynaptic pERK activation and function, showing FMRP and Csw/SHP2 act within the same signaling pathway. Thus, a FMRP and SHP2 MAPK/ERK regulative mechanism controls basal and activity-dependent neurotransmission strength. Public Library of Science 2023-01-26 /pmc/articles/PMC9879533/ /pubmed/36701299 http://dx.doi.org/10.1371/journal.pbio.3001969 Text en © 2023 Leahy et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Leahy, Shannon N.
Song, Chunzhu
Vita, Dominic J.
Broadie, Kendal
FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title_full FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title_fullStr FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title_full_unstemmed FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title_short FMRP activity and control of Csw/SHP2 translation regulate MAPK-dependent synaptic transmission
title_sort fmrp activity and control of csw/shp2 translation regulate mapk-dependent synaptic transmission
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879533/
https://www.ncbi.nlm.nih.gov/pubmed/36701299
http://dx.doi.org/10.1371/journal.pbio.3001969
work_keys_str_mv AT leahyshannonn fmrpactivityandcontrolofcswshp2translationregulatemapkdependentsynaptictransmission
AT songchunzhu fmrpactivityandcontrolofcswshp2translationregulatemapkdependentsynaptictransmission
AT vitadominicj fmrpactivityandcontrolofcswshp2translationregulatemapkdependentsynaptictransmission
AT broadiekendal fmrpactivityandcontrolofcswshp2translationregulatemapkdependentsynaptictransmission