Dysregulation of the fibroblast growth factor system in major depression

Evans, Simon J.; Choudary, Prabhakara V; Neal, Charles R.; Li, J. Z.; Vawter, Marquis P.; Tomita, Hiroaki; López, Juan F.; Thompson, Robert C.; Meng, Fan; Stead, John D.H.; Walsh, David; Myers, R; Bunney, William E.; Watson, Stanley J.; Jones, Edward G.; Akil, Huda

doi:10.1073/pnas.0406788101

Cited by 359 publications

(288 citation statements)

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“…36,37,58,59 Few studies have explored global expression changes between groups of suicides and psychiatrically normal controls, some have however focused on a particular psychiatric diagnosis, such as bipolar disorder or schizophrenia, and included within these groups subjects that died by suicide. [60][61][62][63][64][65][66][67] Sibille et al 51 recently compared expression patterns in BA9 and BA47 of depressed suicides versus psychiatrically normal controls matched on the basis of sex, age, DAVID genes correspond to the total number of unique DAVID annotated genes. The percentage represents the number of differentially expressed genes belonging to a given category over the total number of DAVID annotated genes.…”

Section: Discussionmentioning

confidence: 99%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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The limbic system has consistently been associated with the control of emotions and with mood disorders. The goal of this study was to identify new molecular targets associated with suicide and with major depression using oligonucleotide microarrays in the limbic system (amygdala, hippocampus, anterior cingulate gryus (BA24) and posterior cingulate gyrus (BA29)). A total of 39 subjects were included in this study. They were all male subjects and comprised 26 suicides (depressed suicides = 18, non depressed suicides = 8) and 13 matched controls. Brain gene expression analysis was carried out on human brain samples using the Affymetrix HG U133 chip set. Differential expression in each of the limbic regions showed group-specific patterns of expression, supporting particular neurobiological mechanisms implicated in suicide and depression. Confirmation of genes selected based on their significance and the interest of their function with reverse transcriptase-polymerase chain reaction showed consistently correlated signals with the results obtained in the microarray analysis. Gene ontology analysis with differentially expressed genes revealed an overrepresentation of transcription and metabolism-related genes in the hippocampus and amygdala, whereas differentially expressed genes in BA24 and BA29 were more generally related to RNA-binding, regulation of enzymatic activity and protein metabolism. Limbic expression patterns were most extensively altered in the hippocampus, where processes related to major depression were associated with altered expression of factors involved with transcription and cellular metabolism. Additionally, our results confirm previous evidence pointing to global alteration of gabaergic neurotransmission in suicide and major depression, offering new avenues in the study and possibly treatment of such complex disorders. Overall, these data suggest that specific patterns of expression in the limbic system contribute to the etiology of depression and suicidal behaviors and highlight the role of the hippocampus in major depression.

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Section: Discussionmentioning

confidence: 99%

Patterns of gene expression in the limbic system of suicides with and without major depression

et al. 2007

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“…[1][2][3] Various microarray profiles in mood disorder have been reported that use different microarray platforms, analysis methodology, regional differences, agonal factors and brain pH. [4][5][6][7][8][9][10][11][12][13][14] Presumably, a substantial heterogeneity in the pathophysiology of mood disorder coupled with small sample sizes and small fold changes contributes to the lack of consistency among the findings. 15 In five microarray studies a broad mitochondrial dysfunction was reported in neuropsychiatric disorders.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…13,33 Microarray data analysis Cohort composition for microarray analysis-A control group analysis was conducted by splitting the controls into subgroups at a median pH of 6.87 and comparing the gene expression profile with PLMfit. This analysis was used to evaluate gene expression results for agonal-pH sensitive genes.…”

Section: Oligonucleotide Microarraysmentioning

confidence: 99%

“…13,33 Microarray data analysis Probe level model fit for condensation of affymetrix probe data-A robust probe level model (PLM) fits a linear model to Affymetrix microarray probe data and is freely available at http://www.bioconductor.org. A complete description of the PLM fit algorithm is available at http://www.stat.berkeley.edu/users/bolstad/Dissertation/Bolstad_2004_Dissertation.pdf.…”

Section: Oligonucleotide Microarraysmentioning

confidence: 99%

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Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

et al. 2006

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Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe pathophysiology of depression and mania is largely unknown leaving open a question of which cellular pathway(s) to investigate. Gene expression screening is a powerful method for probing alterations in neural functions in mood disorder. Examining gene expression profiles has been extremely useful for establishing different phenotypes in cancer. [1][2][3] Various microarray profiles in mood disorder have been reported that use different microarray platforms, analysis methodology, regional differences, agonal factors and brain pH. [4][5][6][7][8][9][10][11][12][13][14] Presumably, a substantial heterogeneity in the pathophysiology of mood disorder coupled with small sample sizes and small fold changes contributes to the lack of consistency among the findings. 15 In five microarray studies a broad mitochondrial dysfunction was reported in neuropsychiatric disorders. 10,11,14,[16][17][18] One study of bipolar disorder (BPD) focused on a broad set of mitochondrial-related gene expression and found that in general, mitochondrial gene expression was predominantly decreased in BPD compared to controls in the dorsolateral pre-frontal cortex (DLPFC) when using Stanley samples...

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“…In addition, FGF ligand/FGF ligand and FGFR1/FGFR1 dimerization may expand the spectrum of interactions between FGFs and FGFR affecting their binding and signaling properties [5]. Anomalous FGF signaling is associated with several human diseases, for instance uncontrolled FGF signaling has been linked to the etiology of neurodegenerative disorders, such as major depressive disorder and Parkinson's disease [6].…”

Section: Introductionmentioning

confidence: 99%

Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family

Romero-Fernández

Borroto-Escuela

Tarakanov

et al. 2011

Biochemical and Biophysical Research Communications

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a b s t r a c tFibroblast growth factor receptor 1 (FGFR1) is known to be activated by homodimerization in the presence of both the FGF agonist ligand and heparan sulfate glycosaminoglycan. FGFR1 homodimers in turn trigger a variety of downstream signaling cascades via autophosphorylation of tyrosine residues in the cytoplasmic domain of FGFR1. By means of Bioluminescence Energy Resonance Transfer (BRET) as a sign of FGFR1 homodimerization, we evaluated in HEK293T cells the effects of all known FGF agonist ligands on homodimer formation. A significant correlation between BRET 2 signaling and ERK1/2 phosphorylation was observed, leading to a further characterization of the binding and signaling properties of the FGF subfamilies. FGF agonist ligand-FGFR1 binding interactions appear as the main mechanism for the control of FGFR1 homodimerization and MAPK signaling which demonstrated a high correlation. The bioinformatic analysis demonstrates the interface of the two pro-triplets SSS (Ser-Ser-Ser) and YGS (Tyr-Gly-Ser) located in the extracellular and intracellular domain of the FGFR1. These pro-triplets are postulated participate in the FGFR1 homodimerization interface interaction. The findings also reveal that FGF agonist ligands within the same subfamily of the FGF gene family produced similar increases in FGFR1 homodimer formation and MAPK signaling. Thus, the evolutionary relationship within this gene family appears to have a distinct functional relevance.

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Dysregulation of the fibroblast growth factor system in major depression

Cited by 359 publications

References 40 publications

Patterns of gene expression in the limbic system of suicides with and without major depression

Patterns of gene expression in the limbic system of suicides with and without major depression

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

Agonist-induced formation of FGFR1 homodimers and signaling differ among members of the FGF family

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