Exploring mechanisms of FGF signalling through the lens of structural biology

Goetz, Regina; Mohammadi, Moosa

doi:10.1038/nrm3528

Cited by 488 publications

(489 citation statements)

References 119 publications

(253 reference statements)

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“…Western blot analysis of whole cortices, despite showing an increase in GFAP expression in LOF mutants, did not reveal changes in levels of pERK (30), pAKT (30), NF-κB (3), Cdc42 (31), Lhx2 (32), and pSMAD3 (16) (Fig. S4B).…”

Section: Significancementioning

confidence: 99%

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Kang

Balordi

et al. 2014

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

125

113

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In the brain, astrocytes are multifunctional cells that react to insults and contain damage. However, excessive or sustained reactive astrocytes can be deleterious to functional recovery or contribute to chronic inflammation and neuronal dysfunction. Therefore, astrocyte activation in response to damage is likely to be tightly regulated. Although factors that activate astrocytes have been identified, whether factors also exist that maintain astrocytes as nonreactive or reestablish their nonreactive state after containing damage remains unclear. By using loss-and gainof-function genetic approaches, we show that, in the unperturbed adult neocortex, FGF signaling is required in astrocytes to maintain their nonreactive state. Similarly, after injury, FGF signaling delays the response of astrocytes and accelerates their deactivation. In addition, disrupting astrocytic FGF receptors results in reduced scar size without affecting neuronal survival. Overall, this study reveals that the activation of astrocytes in the normal and injured neocortex is not only regulated by proinflammatory factors, but also by factors such as FGFs that suppress activation, providing alternative therapeutic targets.brain damage | astrogliosis A strocytes are the most abundant cell type in the mammalian brain. The thin processes of protoplasmic astrocytes (graymatter astrocytes) canvas the neural parenchyma and make contact with several other cell types. Protoplasmic astrocytes carry out a variety of functions, including maintaining the bloodbrain barrier, ion homeostasis, neurotransmitter turnover, and synapse formation (1). Another major function of these astrocytes involves their activation in response to damage. Astrocyte activation, or astrogliosis, plays a central role in the response to most or all neurological insults including trauma, infections, stroke, tumorigenesis, neurodegeneration, and epilepsy. The extent of astrogliosis can influence long-term recovery, and the response of astrocytes to different insults is likely to be graded and complex (2, 3). Nevertheless, in most cases, astrocytes transiently become hypertrophic and express high levels of intermediate filaments such as GFAP, vimentin, tenascin C, and nestin, and, in cases of severe damage, astrocytes can also become proliferative and form a scar.Astrogliosis can have beneficial and detrimental effects on recovery. Astrogliosis is essential for minimizing the spread of damage and inflammation, but it is also inhibitory for axonal and cellular regeneration. For example, in transgenic mice in which reactive astrocytes are ablated or disabled, traumatic injury leads to the lack of normal scar formation, prolonged and more widespread inflammation, and a failure to reconstruct the bloodbrain barrier and maintain tissue integrity (4, 5). However, ablation or impairment of reactive astrocytes also leads to increased nerve fiber growth in the immediate vicinity of the injury site, which could improve axonal regeneration and functional recovery (4, 5). Therefore, levels of astrocy...

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Section: Significancementioning

confidence: 99%

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Kang

Balordi

et al. 2014

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

125

113

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“…Binding of FGF ligands to FGFRs induces dimerization and juxtaposition of the tyrosine kinase domains to initiate the sequential transphosphorylation of at least six tyrosine residues (Furdui et al 2006;Goetz and Mohammadi 2013;Ornitz and Itoh 2015). Activation of the FGFR tyrosine kinase domain allows the direct phosphorylation of the docked adaptor protein FGFR substrate 2α (FRS2α) and binding of other adaptor proteins, including phospholipase Cγ (PLCγ), signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 (Ornitz and Itoh 2015).…”

Section: Fgf Signalingmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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“…FGF9 is primarily expressed by neurons in the cortex, hippocampus, thalamus, cerebellum, and spinal cord (16)(17)(18)(19)(20), although it is also expressed by glia in the hindbrain and spinal cord (21). FGF9 interacts with several of the tyrosine kinase FGF receptors (FGFR) (22), binding preferentially to FGFR3 (23). Functionally, the literature suggests that FGF9 may promote cell survival.…”

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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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Exploring mechanisms of FGF signalling through the lens of structural biology

Cited by 488 publications

References 119 publications

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Astrocyte activation is suppressed in both normal and injured brain by FGF signaling

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor 9 is a novel modulator of negative affect

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