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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Public Library of Science
2023
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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 |
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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 |
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