Sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (FGF14), a regulator of neuronal ion channels

Mark L. Sowers, Jessica Di Re, Paul A. Wadsworth, Alexander S. Shavkunov, Cheryl Lichti, Kangling Zhang, Fernanda Laezza

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Article number5
JournalProteomes
Volume7
Issue number1
DOIs
StatePublished - Mar 1 2019

Fingerprint

Ion Channels
Proteomics
Schizophrenia
Proteome
Cyclic AMP-Dependent Protein Kinases
gamma-Aminobutyric Acid
Antipsychotic Agents
Labels
Dopamine
Animals
Proteins
Synaptic Transmission
Genes
Association reactions
Endophenotypes
Dopamine Receptors
Hippocampus
fibroblast growth factor 14
Genome
Phenotype

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 journalArticle

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. In: Proteomes. 2019 ; Vol. 7, No. 1.
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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.",
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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

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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.

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KW - Excitatory/inhibitory tone

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KW - Mass spectroscopy

KW - Schizophrenia

KW - Sex-specific differences

KW - Synaptic plasticity

KW - Voltage gated channels

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