Self-secretion of fibroblast growth factor-9 supports basal forebrain cholinergic neurons in an autocrine/paracrine manner

Kanda, Takashi; Iwasaki, Tsuneto; Nakamura, Satoshi; Kurokawa, Tsutomu; Ikeda, Kazuhiko; Mizusawa, Hidehiro

doi:10.1016/s0006-8993(00)02563-4

Cited by 41 publications

(25 citation statements)

References 36 publications

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“…Functionally, the literature suggests that FGF9 may promote cell survival. For example, FGF9 acts as a survival factor for nigrostriatal and mesencephalic dopamine neurons (24), and FGF9 treatment can increase the survival and soma size of cultured basal forebrain cholinergic neurons (25). FGF9 also weakly promoted proliferation and survival of cultured adult subventricular neural progenitor cells, inhibiting astrocyte differentiation (26).…”

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confidence: 99%

Fibroblast growth factor 9 is a novel modulator of negative affect

Aurbach

Inui

Turner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety-and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.fibroblast growth factor 9 | major depression | anxiety | hippocampus | affect T he neurotrophic hypothesis of major depressive disorder (MDD) posits that the neurobiological basis for mood disorders may be due to the dysregulation of growth factors and their effects on brain circuitry (1, 2). This hypothesis is supported by gene expression profiling experiments in postmortem human brains that implicate the fibroblast growth factor (FGF) family and other neurotrophins in MDD (3, 4). To date, only a few growth factors involved in mood disorders, such as brain-derived neurotrophic factor (BDNF) and FGF2, have been studied extensively.Our laboratory and others have demonstrated that FGF2 is down-regulated in the frontal cortices (3), hippocampus (5), and locus coeruleus (4) in depressed individuals. This consistent decrease in FGF2 expression across regions is striking and underscores the likely importance of FGF2 in mediating affect.Follow-up studies from our laboratory and others have focused on the FGF family and have demonstrated a key role of FGF2 in the control of emotional behavior. Rats exposed to chronic social defeat stress, an animal model recapitulating some aspects of MDD, showed decreased hippocampal FGF2 expression relative to unstressed controls (6), whereas subchronic and chronic administration of FGF2 had antidepressant properties (7,8). Moreover, adminis...

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confidence: 99%

Fibroblast growth factor 9 is a novel modulator of negative affect

Aurbach

Inui

Turner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Likewise, in the FGF family, FGF-9 in particular was increased by HIV and the increase was reversed by NGF. FGF-9 has been shown to be secreted from neurons and to support survival of basal forebrain cholinergic neurons (Kanda et al 2000). However, more work needs to be done to understand the importance of these factors in the context of HIV neuropathogenesis.…”

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Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

Williams¹,

Killebrew

Clary

et al. 2015

J Neuroimmune Pharmacol

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Macrophage and microglial activation by HIV in the central nervous system (CNS) triggers the secretion of soluble factors which damage neurons. Therapeutic approaches designed to restore cognitive function by suppressing this inflammatory activity have not yet been successful. Recent studies have indicated that the phenotype of macrophages is differentially controlled by the mature and pro form of nerve growth factor. These cells therefore may be highly responsive to the imbalance in pro versus mature neurotrophins often associated with neurodegenerative diseases. In this study we evaluated the interactions between neurotrophins and HIV induced macrophage activation. HIV stimulation of macrophages induced a neurotoxic phenotype characterized by the expression of podosomes, suppression of calcium spiking and increased neurotoxin production. The secretome of the activated macrophages revealed a bias toward anti-angiogenic like activity and increased secretion of MMP-9. Co-stimulation with NGF and HIV suppressed neurotoxin secretion, increased calcium spiking, suppressed podosome expression and reversed 86% of the proteins secreted in response to HIV, including MMP-9 and many growth factors. In contrast, co-stimulation of macrophages with proNGF not only failed to reverse the effects of HIV but increased the neurotoxic phenotype. These differential effects of proNGF and NGF on HIV activation provide a potential novel therapeutic avenue for controlling macrophage activation in response to HIV.

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“…1 a potent mitogen and survival factor for numerous cell types (1)(2)(3)(4)(5)(6), belongs to a heparin-binding polypeptide family that consists of at least 23 structurally related proteins (7,8). Expression of FGF9 plays critical roles in sex determination, bone formation, neuron development, lens fiber differentiation, and gap junction formation (4, 9 -12).…”

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The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

Wing

Chen

Chuang

et al. 2005

Journal of Biological Chemistry

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Fibroblast growth factor-9 (FGF9) is a potent mitogen that stimulates normal and cancer cell proliferation though the signaling mechanism is not fully understood. In this study, we aimed to unravel the signaling cascades mediate FGF9 actions in human uterine endometrial stromal cell. Our results demonstrate that the mitogenic effect of FGF9 is transduced via two parallel but additive signaling pathways involving mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase. Activation of mTOR by FGF9 induces p70 ribosomal S6 kinase (S6K1) phosphorylation, cyclin expression, and cell proliferation, which are independent of phosphatidylinositol 3-kinase and Akt. Coimmunoprecipitation analysis demonstrates that mTOR physically associates with S6K1 upon FGF9 treatment, whereas ablation of mTOR activity using RNA interference or pharmacological inhibitor blocks S6K1 phosphorylation and cell proliferation induced by FGF9. Further study demonstrates that activation of mTOR is regulated by a phospholipase C␥-controlled calcium signaling pathway. These studies provide evidence to demonstrate, for the first time, that a novel signaling cascade involving phospholipase C␥, calcium, mTOR, and S6K1 is activated by FGF9 in a receptor-specific manner.Fibroblast growth factor-9 (FGF9), 1 a potent mitogen and survival factor for numerous cell types (1-6), belongs to a heparin-binding polypeptide family that consists of at least 23 structurally related proteins (7,8). Expression of FGF9 plays critical roles in sex determination, bone formation, neuron development, lens fiber differentiation, and gap junction formation (4, 9 -12). Null-allele mice lacking FGF9 exhibit severe lung hypoplasia and die shortly after birth (4). On the other hand, aberrant expression of FGF9 is associated with the development of several human diseases including prostate cancer, brain tumor, and endometriosis (3, 6, 13). Despite its well studied biological functions, the signaling mechanism of FGF9 remains to be identified.The signaling of FGF is mediated via complex interactions between specific members of the FGF family and one or more FGF receptor isoforms. Receptors for FGF (FGFR1 to -4) are tyrosine kinase receptors consisting of two intracellular tyrosine kinase domains, a single transmembrane domain, and an extracellular portion that contains three immunoglobulin-like (Ig) domains. The third Ig domain (Ig III), which exerts the highest impact on FGF receptor binding specificity and tissuespecific expression patterns, is the region in which alternative splicing occurs. Three different splice variants (designated as IIIa, IIIb, and IIIc) have been identified for FGFR1 and FGFR2, whereas only the IIIb and IIIc variants have been detected for FGFR3 (14 -17). As of yet, no splice variant for FGFR4 has been identified. The splicing variant "IIIa" of FGFR is a secreted protein, whereas IIIb and IIIc are both membrane-bound receptors containing mutually exclusive Ig III domains. It is generally believed that the IIIb isoform of FGFRs is ex...

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Self-secretion of fibroblast growth factor-9 supports basal forebrain cholinergic neurons in an autocrine/paracrine manner

Cited by 41 publications

References 36 publications

Fibroblast growth factor 9 is a novel modulator of negative affect

Fibroblast growth factor 9 is a novel modulator of negative affect

Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation

The Mammalian Target of Rapamycin-p70 Ribosomal S6 Kinase but Not Phosphatidylinositol 3-Kinase-Akt Signaling Is Responsible for Fibroblast Growth Factor-9-induced Cell Proliferation

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