Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

Turner, Cortney A.; Eren-Koçak, Emine; Inui, Edny Gula; Watson, Stanley J.; Akil, Huda

doi:10.1016/j.semcdb.2015.10.003

Cited by 58 publications

(54 citation statements)

References 100 publications

(103 reference statements)

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“…FGF signaling plays a ubiquitous role in development, especially in brain development and cell fate [36]. However, diversity and specificity is acquired by combination of different receptors isoforms [13] and ligands reaching a maximum level of complexity depending on cell type, cell context and signalling kinetics.…”

Section: Discussionmentioning

confidence: 99%

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Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

et al. 2016

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Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modelling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1%) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19%; p<0.0001) and hotspot BRAF p.V600E (12/53; 22.6%) (p<0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.

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Section: Discussionmentioning

confidence: 99%

“…multinodular growth). Importantly, the presence of specific FGFR1 mutations point the way towards existing targeted therapies for children and adults with recurrent or difficult-to-excise tumors [8,9,35,36]. Such therapies could also prove effective in those tumors resistant to conventional anti-seizure treatments.…”

Section: Discussionmentioning

confidence: 99%

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

et al. 2016

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“…FGF9 has been reported to involve in neuronal disorders [13,14]. In neurodegenerative diseases, FGF9 signaling has been reported to affect cellular or pathological features in Alzheimer's disease (AD) and Parkinson's disease (PD) [5,[15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington’s Disease

Yusuf

Cheng

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Huntington’s disease (HD) is a heritable neurodegenerative disorder, and there is no cure for HD to date. A type of fibroblast growth factor (FGF), FGF9, has been reported to play prosurvival roles in other neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. However, the effects of FGF9 on HD is still unknown. With many similarities in the cellular and pathological mechanisms that eventually cause cell death in neurodegenerative diseases, we hypothesize that FGF9 might provide neuroprotective functions in HD. Methods: In this study, STHdh^Q7/Q7 (WT) and STHdh^Q111/Q111 (HD) striatal knock-in cell lines were used to evaluate the neuroprotective effects of FGF9. Cell proliferation, cell death and neuroprotective markers were determined via the MTT assay, propidium iodide staining and Western blotting, respectively. The signaling pathways regulated by FGF9 were demonstrated using Western blotting. Additionally, HD transgenic mouse models were used to further confirm the neuroprotective effects of FGF9 via ELISA, Western blotting and immunostaining. Results: Results show that FGF9 not only enhances cell proliferation, but also alleviates cell death as cells under starvation stress. In addition, FGF9 significantly upregulates glial cell line-derived neurotrophic factor (GDNF) and an anti-apoptotic marker, Bcl-xL, and decreases the expression level of an apoptotic marker, cleaved caspase 3. Furthermore, FGF9 functions through ERK, AKT and JNK pathways. Especially, ERK pathway plays a critical role to influence the effects of FGF9 toward cell survival and GDNF production. Conclusions: These results not only show the neuroprotective effects of FGF9, but also clarify the critical mechanisms in HD cells, further providing an insight for the therapeutic potential of FGF9 in HD.

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“…Post‐mortem analyses of these same brain regions implicate several genes correlating with MDD but the most significantly dysregulated genes in MDD patients belong to the fibroblast growth factor (FGF) family (Turner et al . ). Microarray hybridization studies of the dorsolateral prefrontal cortex region of MDD patients show that the ligand FGF9 is up‐regulated relative to controls while the ligand FGF2 and the FGF receptors (FGFR2 and FGFR3) are down‐regulated (Evans et al .…”

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confidence: 97%

Fibroblast growth factor 2 regulates activity and gene expression of human post‐mitotic excitatory neurons

Gupta

M‐Redmond

Meng

et al. 2017

Journal of Neurochemistry

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Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to model mature, postmitotic excitatory neurons and examine effects of FGF2. FGF2 gene expression is known to be altered in brain regions of major depressive disorder (MDD) patients and FGF2 has anti-depressive effects in animal models of depression. We generated stable inducible neurons (siNeurons) conditionally expressing human neurogenin 2 (NEUROG2) to generate a homogenous population of post-mitotic excitatory neurons and study the functional as well as the transcriptional effects of FGF2. Upon induction of NEUROG2 with doxycycline, the vast majority of cells are post-mitotic, and the gene expression profile recapitulates that of excitatory neurons within 6 days. Using hES cell lines that inducibly express NEUROG2 as well as GCaMP6f, we were able to characterize spontaneous calcium activity in these neurons and show that calcium transients increase in the presence of FGF2. The FGF2-responsive genes were determined by RNA-Seq. FGF2-regulated genes previously identified in non-neuronal cell types were upregulated (EGR1, ETV4, SPRY4, and DUSP6) as a result of chronic FGF2 treatment of siNeurons. Novel neuron specific genes were also identified that may mediate FGF2-dependent increases in synaptic efficacy including NRXN3, SYT2, and GALR1. Since several of these genes have been implicated in MDD previously, these results will provide the basis for more mechanistic studies of the role of FGF2 in MDD.

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Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

Cited by 58 publications

References 100 publications

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors

Fibroblast Growth Factor 9 Suppresses Striatal Cell Death Dominantly Through ERK Signaling in Huntington’s Disease

Fibroblast growth factor 2 regulates activity and gene expression of human post‐mitotic excitatory neurons

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