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Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels
Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14(−/−) mice recapitulate the salient endophenotypes of synaptic dysfunction and beha...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473632/ https://www.ncbi.nlm.nih.gov/pubmed/30678040 http://dx.doi.org/10.3390/proteomes7010005 |
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author | Sowers, Mark L. Di Re, Jessica Wadsworth, Paul A. Shavkunov, Alexander S. Lichti, Cheryl Zhang, Kangling Laezza, Fernanda |
author_facet | Sowers, Mark L. Di Re, Jessica Wadsworth, Paul A. Shavkunov, Alexander S. Lichti, Cheryl Zhang, Kangling Laezza, Fernanda |
author_sort | Sowers, Mark L. |
collection | PubMed |
description | Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14(−/−) mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14(−/−) model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14(+/+) and Fgf14(−/−) mice. We discovered that all of the differentially expressed proteins measured in Fgf14(−/−) animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14(−/−) mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14(−/−) mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14(−/−) mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy. |
format | Online Article Text |
id | pubmed-6473632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64736322019-04-29 Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels Sowers, Mark L. Di Re, Jessica Wadsworth, Paul A. Shavkunov, Alexander S. Lichti, Cheryl Zhang, Kangling Laezza, Fernanda Proteomes Article Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14(−/−) mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14(−/−) model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14(+/+) and Fgf14(−/−) mice. We discovered that all of the differentially expressed proteins measured in Fgf14(−/−) animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14(−/−) mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14(−/−) mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14(−/−) mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy. MDPI 2019-01-23 /pmc/articles/PMC6473632/ /pubmed/30678040 http://dx.doi.org/10.3390/proteomes7010005 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Sowers, Mark L. Di Re, Jessica Wadsworth, Paul A. Shavkunov, Alexander S. Lichti, Cheryl Zhang, Kangling Laezza, Fernanda Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title | Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title_full | Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title_fullStr | Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title_full_unstemmed | Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title_short | Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels |
title_sort | sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (fgf14), a regulator of neuronal ion channels |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473632/ https://www.ncbi.nlm.nih.gov/pubmed/30678040 http://dx.doi.org/10.3390/proteomes7010005 |
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