Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | 5 |
| Journal | Proteomes |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| State | Published - Mar 1 2019 |
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Keywords
- Alzheimer's Disease
- Autism
- Bioinformatics
- Cognitive impairment
- Excitatory/inhibitory tone
- FGF14
- Mass spectroscopy
- Schizophrenia
- Sex-specific differences
- Synaptic plasticity
- Voltage gated channels
ASJC Scopus subject areas
- Structural Biology
- Biochemistry
- Molecular Biology
- Clinical Biochemistry
Cite this
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.
In: Proteomes, Vol. 7, No. 1, 5, 01.03.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (FGF14), a regulator of neuronal ion channels
AU - Sowers, Mark L.
AU - Di Re, Jessica
AU - Wadsworth, Paul A.
AU - Shavkunov, Alexander S.
AU - Lichti, Cheryl
AU - Zhang, Kangling
AU - Laezza, Fernanda
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - Alzheimer's Disease
KW - Autism
KW - Bioinformatics
KW - Cognitive impairment
KW - Excitatory/inhibitory tone
KW - FGF14
KW - Mass spectroscopy
KW - Schizophrenia
KW - Sex-specific differences
KW - Synaptic plasticity
KW - Voltage gated channels
UR - http://www.scopus.com/inward/record.url?scp=85066451410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066451410&partnerID=8YFLogxK
U2 - 10.3390/proteomes7010005
DO - 10.3390/proteomes7010005
M3 - Article
VL - 7
JO - Proteomes
JF - Proteomes
SN - 2227-7382
IS - 1
M1 - 5
ER -