FGFR1
Fibroblast growth factor receptor 1 precursor (EC 2.7.10.1) (FGFR-1) (Basic fibroblast growth factor receptor 1) (BFGFR) (bFGF-R-1) (Fms-like tyrosine kinase 2) (FLT-2) (N-sam) (Proto-oncogene c-Fgr) (CD331 antigen) [BFGFR] [CEK] [FGFBR] [FLG] [FLT2] [HBGFR]
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The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that β-amyloid (Aβ) accumulation is a key element. It follows that clearing the brain of Aβ would be beneficial, which has not been the case. Therefore, Aβ is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor β-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with Aβ. Protein data bank (pdb) entries for klotho and Aβ were searched on the RCSB Protein Data Bank for β-KL and AD amyloid β-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the Aβ and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of Aβ. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog ([i]Xenopus tropicalis[/i]), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of Aβ suggests that Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.
Keywords
- Alzheimer’s disease
- HSV-1
- aging
- alignment
- klotho
- neurodegeneration
- neuroinflammation
- protein
- ubiquitin
- β-amyloid
Cellular senescence can be triggered by various intrinsic and extrinsic stimuli. We previously reported that silencing of 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) induces cellular senescence through augmented fibroblast growth factor receptor 1 (FGFR1) signaling. However, the exact molecular mechanism connecting heparan sulfation and cellular senescence remains unclear. Here, we investigated the potential involvement of heparan sulfate proteoglycans (HSPGs) in augmented FGFR1 signaling and cellular senescence. Depletion of several types of HSPGs revealed that cells depleted of syndecan 1 (SDC1) exhibited typical senescence phenotypes, and those depleted of PAPSS2-, SDC1-, or heparan sulfate 2-O sulfotransferase 1 (HS2ST1) showed decreased FGFR1 internalization along with hyperresponsiveness to and prolonged activation of fibroblast growth factor 2 (FGF2)-stimulated FGFR1- v-akt murine thymoma viral oncogene homolog (AKT) signaling. Clathrin- and caveolin-mediated FGFR1 endocytosis contributed to cellular senescence through the FGFR1-AKT-p53-p21 signaling pathway. Dynasore treatment triggered senescence phenotypes, augmented FGFR1-AKT-p53-p21 signaling, and decreased SDC1 expression. Finally, the replicatively and prematurely senescent cells were characterized by decreases of SDC1 expression and FGFR1 internalization, and an increase in FGFR1-AKT-p53-p21 signaling. Together, our results demonstrate that properly sulfated SDC1 plays a critical role in preventing cellular senescence through the regulation of FGFR1 endocytosis.
Keywords
- FGFR1
- SDC1
- cellular senescence
- endocytosis
- heparan sulfation
Perturbation in cell adhesion and growth factor signalling in satellite cells results in decreased muscle regenerative capacity. Cdon (also called Cdo) is a component of cell adhesion complexes implicated in myogenic differentiation, but its role in muscle regeneration remains to be determined. We generated inducible satellite cell-specific Cdon ablation in mice by utilizing a conditional Cdon allele and Pax7 . To induce Cdon ablation, mice were intraperitoneally injected with tamoxifen (tmx). Using cardiotoxin-induced muscle injury, the effect of Cdon depletion on satellite cell function was examined by histochemistry, immunostaining, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Isolated myofibers or myoblasts were utilized to determine stem cell function and senescence. To determine pathways related to Cdon deletion, injured muscles were subjected to RNA sequencing analysis. Satellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis, likely attributable to decreased proliferation, and senescence, of satellite cells. Cultured Cdon-depleted myofibers exhibited 32 ± 9.6% of EdU-positive satellite cells compared with 58 ± 4.4% satellite cells in control myofibers (P < 0.05). About 32.5 ± 3.7% Cdon-ablated myoblasts were positive for senescence-associated β-galactosidase (SA-β-gal) while only 3.6 ± 0.5% of control satellite cells were positive (P < 0.001). Transcriptome analysis of muscles at post-injury Day 4 revealed alterations in genes related to mitogen-activated protein kinase signalling (P < 8.29 e ) and extracellular matrix (P < 2.65 e ). Consistent with this, Cdon-depleted tibialis anterior muscles had reduced phosphorylated extracellular signal-regulated kinase (p-ERK) protein levels and expression of ERK targets, such as Fos (0.23-fold) and Egr1 (0.31-fold), relative to mock-treated control muscles (P < 0.001). Cdon-depleted myoblasts exhibited impaired ERK activation in response to basic fibroblast growth factor. Cdon ablation resulted in decreased and/or mislocalized integrin β1 activation in satellite cells (weak or mislocalized integrin1 in tmx = 38.7 ± 1.9%, mock = 21.5 ± 6%, P < 0.05), previously linked with reduced fibroblast growth factor (FGF) responsiveness in aged satellite cells. In mechanistic studies, Cdon interacted with and regulated cell surface localization of FGFR1 and FGFR4, likely contributing to FGF responsiveness of satellite cells. Satellite cells from a progeria model, Zmpste24 myofibers, showed decreased Cdon levels (Cdon-positive cells in Zmpste24 = 63.3 ± 11%, wild type = 90 ± 7.7%, P < 0.05) and integrin β1 activation (weak or mislocalized integrin β1 in Zmpste24 = 64 ± 6.9%, wild type = 17.4 ± 5.9%, P < 0.01). Cdon deficiency in satellite cells causes impaired proliferation of satellite cells and muscle regeneration via aberrant integrin and FGFR signalling.
Keywords
- Cdon
- Cellular senescence
- FGFR
- Growth factor signalling
- Muscle regeneration
- Satellite cell
Adipose-derived mesenchymal stem cells (ASCs) exhibit great potential in regenerative medicine, and in vitro expansion is frequently necessary to obtain a sufficient number of ASCs for clinical use. Fibroblast growth factor 2 (FGF2) is a common supplement in the ASC culture medium to enhance cell proliferation. To achieve clinical applicability of ASC-based products, prolonged culture of ASCs is sometimes required to obtain sufficient quantity of ASCs. However, the effect of FGF2 on ASCs during prolonged culture has not been previously determined. In this study, ASCs were subjected to prolonged in vitro culture with or without FGF2. FGF2 maintained the small cell morphology and expedited proliferation kinetics in early ASC passages. After prolonged in vitro expansion, FGF2-treated ASCs exhibited increased cell size, arrested cell proliferation, and increased cellular senescence relative to the control ASCs. We observed an upregulation of FGFR1c and enhanced expression of downstream STAT3 in the initial passages of FGF2-treated ASCs. The application of an FGFR1 or STAT3 inhibitor effectively blocked the enhanced proliferation of ASCs induced by FGF2 treatment. FGFR1c upregulation and enhanced STAT3 expression were lost in the later passages of FGF2-treated ASCs, suggesting that the continuous stimulation of FGF2 becomes ineffective because of the refractory downstream FGFR1 and the STAT3 signaling pathway. In addition, no evidence of tumorigenicity was noted in vitro and in vivo after prolonged expansion of FGF2-cultured ASCs. Our data indicate that ASCs have evolved a STAT3-dependent response to continuous FGF2 stimulation which promotes the initial expansion but limits their long-term proliferation.
Keywords
- cell proliferation
- cellular senescence
- fibroblast growth factor 2
- long-term culture
- mesenchymal stem cell
Social isolation predominantly occurs in elderly people and it is strongly associated with cognitive decline. However, the mechanisms that produce isolation-related cognitive dysfunction during aging remain unclear. Here, we evaluated the cognitive, electrophysiological, and morphological effects of short- (4 weeks) and long-term (12 weeks) social isolation in aged male Wistar rats. Long-term but not short-term social isolation increased the plasma corticosterone levels and impaired spatial memory in the Morris water maze. Moreover, isolated animals displayed dampened hippocampal long-term potentiation in vivo, both in the dentate gyrus (DG) and CA1, as well as a specific reduction in the volume of the stratum oriens and spine density in CA1. Interestingly, social isolation induced a transient increase in hippocampal basic fibroblast growth factor (FGF2), whereas fibroblast growth factor receptor 1 (FGFR1) levels only increased after long-term isolation. Importantly, subchronic systemic administration of FGL, a synthetic peptide that activates FGFR1, rescued spatial memory in long-term isolated rats. These findings provide new insights into the neurobiological mechanisms underlying the detrimental effects on memory of chronic social isolation in the aged.
MeSH Terms
- Aging
- Animals
- Cognition
- Cognitive Dysfunction
- Corticosterone
- Fibroblast Growth Factor 2
- Hippocampus
- Long-Term Potentiation
- Male
- Maze Learning
- Peptides
- Rats, Wistar
- Receptor, Fibroblast Growth Factor, Type 1
- Social Isolation
- Spatial Memory
- Time Factors
Keywords
- Cognition
- Corticosterone
- FGF
- Hippocampus
- LTP
- Stress
Caloric restriction (CR) suppresses age-related pathophysiology and extends lifespan. We recently reported that metabolic remodeling of white adipose tissue (WAT) plays an important role in the beneficial actions of CR; however, the detailed molecular mechanisms of this remodeling remain to be established. In the present study, we aimed to identify CR-induced alterations in the expression of fibroblast growth factor 21 (FGF21), a regulator of lipid and glucose metabolism, and of its downstream signaling mediators in liver and WAT, across the lifespan of rats. We evaluated groups of rats that had been either fed ad libitum or calorie restricted from 3 months of age and were euthanized at 3.5, 9, or 24 months of age, under fed and fasted conditions. The expression of FGF21 mRNA and/or protein increased with age in liver and WAT. Interestingly, in the WAT of 9-month-old fed rats, CR further upregulated FGF21 expression and eliminated the aging-associated reductions in the expression of FGFR1 and beta-klotho (KLB; FGF21 receptor complex). It also enhanced the expression of FGF21 targets, including glucose transporter 1 and peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α. The analysis of transcriptional regulators of Fgf21 suggested that aging and CR might upregulate Fgf21 expression via different mechanisms. In adipocytes in vitro, constitutive FGF21 overexpression upregulated the FGF21 receptor complex and FGF21 targets at the mRNA or protein level. Thus, both aging and CR induced FGF21 expression in rat WAT; however, only CR activated FGF21 signaling. Our results suggest that FGF21 signaling contributes to the CR-induced metabolic remodeling of WAT, likely activating glucose uptake and mitochondrial biogenesis.
MeSH Terms
- 3T3-L1 Cells
- Adipose Tissue, White
- Aging
- Animals
- Caloric Restriction
- Fibroblast Growth Factors
- Glucose Transporter Type 1
- Male
- Mice
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Rats
- Rats, Wistar
- Signal Transduction
Keywords
- Caloric restriction
- Fibroblast growth factor 21
- Glucose transporter 1
- White adipose tissue
- β-Klotho
Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknown. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together, these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons and other cells types as a metabolic substrate.
MeSH Terms
- Animals
- Astrocytes
- Brain
- Energy Metabolism
- Glucuronidase
- Glycolysis
- Mice
- Mice, Inbred C57BL
- Neurons
- Oxygen
Keywords
- Energy metabolism
- aging
- astrocytes
- lactate
- neuronal-glial interaction
Neuroblasts exist within the human subependymal zone (SEZ); however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We found evidence of dividing cells in the human SEZ (n D 50) in conjunction with a dramatic age-related decline (21-103 years) of mRNAs indicative of proliferating cells (Ki67) and immature neurons (doublecortin). Microglia mRNA (ionized calcium-binding adapter molecule 1) increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1), astrocytes (vimentin and pan-glial fibrillary acidic protein), and oligodendrocytes (oligodendrocyte lineage transcription factor 2) remained stable. Epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF2) mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα), EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4) and FGF receptor 1 (FGFR1) mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte marker expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2, and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.
Keywords
- aging
- doublecortin
- gliogenesis
- human
- neurogenesis
- proliferation
- subventricular zone
FGF-2 stimulates preosteoblast replication, and knockout of the FGF-2 gene in mice resulted in osteopenia with age, associated with decreased Wnt-β-Catenin signaling. In addition, targeted expression of FGF-2 in osteoblast progenitors increased bone mass in mice via Wnt-β-Catenin signaling. We posited that diminution of the intrinsic proliferative capacity of human mesenchyme-derived progenitor cells (HMDPCs) with age is due in part to reduction in FGF-2. To test this hypothesis HMDPCs from young (27-38), middle aged (47-56), and old (65-76) female human subjects were isolated from bone discarded after orthopedic procedures. HMDPCs cultures were mostly homogeneous with greater than 90% mesenchymal progenitor cells, determined by fluorescence-activated cell sorting. There was a progressive decrease in FGF-2 and FGFR1 mRNA and protein in HMDPCs with age. Since FGF-2 activates β-catenin, which can enhance bone formation, we also assessed its age-related expression in HMDPCs. An age-related decrease in total-β-Catenin mRNA and protein expression was observed. However there were increased levels of p-β-Catenin and decreased levels of activated-β-Catenin in old HMDSCs. FGF-2 treatment increased FGFR1 and β-Catenin protein, reduced the level of p-β-Catenin and increased activated-β-Catenin in aged HMDPCs. In conclusion, reduction in FGF-2 expression could contribute to age-related impaired function of HMDPCs via modulation of Wnt-β-catenin signaling.
MeSH Terms
- Adult
- Aged
- Aging
- Cells, Cultured
- Female
- Fibroblast Growth Factor 2
- Gene Expression
- Humans
- Mesenchymal Stem Cells
- Middle Aged
- Receptor, Fibroblast Growth Factor, Type 1
- Wnt Signaling Pathway
- Young Adult
- beta Catenin
Keywords
- AGING
- ENDOGENOUS FIBROBLAST GROWTH FACTOR-2
- FIBROBLAST GROWTH FACTOR RECEPTOR
- HUMAN MESENCHYME-DERIVED PROGENITOR CELLS
- β-CATENIN
The objective of this study was to investigate α-Klotho and fibroblast growth factor receptor 1 (FGFR1) expression in hyperplastic parathyroid glands, as well as their role in the development of renal hyperparathyroidism. Hyperplastic parathyroid glands (n = 90) were obtained from 24 patients who received parathyroidectomy due to secondary renal hyperparathyroidism. Normal parathyroid tissue was obtained from glands (n = 6) that were inadvertently removed, in conjunction with thyroidectomy, from patients with thyroid carcinoma. The expression of α-Klotho and FGFR1 in the parathyroid tissue was detected using immunohistochemical staining. The expression of α-Klotho and FGFR1 was significantly reduced in the hyperplastic parathyroid tissue compared to that in the normal parathyroid tissue. The expression of α-Klotho decreased further with increasing parathyroid pathology. A significant positive correlation was observed between α-Klotho and FGFR1 (r = 0.38, P < 0.01). FGFR1 (r = -0.21, P < 0.05) and α-Klotho (r = -0.42, P < 0.01) were negatively correlated with the volume of the hyperplastic parathyroid tissue. The expression of α-Klotho and FGFR1 decreases in the parathyroid glands of dialysis patients with secondary hyperparathyroidism, and this decrease may play an important role in the pathogenesis of secondary renal hyperparathyroidism.
MeSH Terms
- Adult
- Aged
- Aging
- Female
- Follow-Up Studies
- Glucuronidase
- Humans
- Hyperparathyroidism, Secondary
- Hyperplasia
- Immunohistochemistry
- Kidney Failure, Chronic
- Male
- Middle Aged
- Parathyroid Glands
- Receptor, Fibroblast Growth Factor, Type 1
- Renal Dialysis
- Retrospective Studies
- Time Factors
Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes--FGFR1, PMP22, and CDKN1A--that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.
MeSH Terms
- Aged
- Aging
- Animals
- Biomarkers, Tumor
- Decision Trees
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Genes, Neoplasm
- Humans
- Male
- Mice
- Middle Aged
- Models, Biological
- Prognosis
- Prostatic Neoplasms
- RNA, Messenger
- Reproducibility of Results
- Species Specificity
To explore the correlation of pulmonary expressions of fibroblast growth factor receptors (FGFR1-4) with lung fibrosis and aging. Real-time fluorescence quantitative PCR was used to detect the expression levels of FGFR1-4 in the lung tissues, and lung fibrosis was observed by HE and Masson staining in mice at different ages. The 4 subtypes of FGFR showed different expression levels in the lung tissues of mice, and FGFR2 had the highest expressions. The expression levels of all the 4 FGFR subtypes in 8-month-old mice were significantly lower than those in 5-week-old mice. The 8-month-old mice tended to present with histological changes of lung fibrosis. FGFR expressions is down-regulated with aging in mice. Among the FGFR subtypes, FGFR2 is expressed at the highest level. The occurrence of lung fibrosis with aging is probably associated with down-regulated FGFR expression. FGF/FGFR signaling may participate in the aging process and regulation of lung fibrosis.
MeSH Terms
- Aging
- Animals
- Lung
- Male
- Mice
- Mice, Inbred C57BL
- Pulmonary Fibrosis
- Receptors, Fibroblast Growth Factor
- Signal Transduction
Fibroblast growth factors (FGFs) promote axon growth during development and regeneration of the nervous system. Among the four types of FGF receptors (FGFRs), FGFR1 is expressed in adult sensory neurons of dorsal root ganglia (DRG), and overexpression of FGFR1 promotes FGF-2-induced elongative axon growth in vitro. Ligand-induced activation of FGFR1 is followed by endocytosis and lysosomal degradation, which leads to the termination of receptor signaling. We previously reported that the lysosomal inhibitor leupeptin enhances FGF-2-induced elongative axon growth of adult DRG neurons overexpressing FGFR1. To better understand the role of subcellular localization of FGFR1 in axon growth, we analyzed the effects of inhibition of endocytosis of FGFR1 on FGF-2-induced neurite outgrowth in PC12 pheochromocytoma cells and adult DRG neurons. The endocytosis inhibitors methyl-β-cyclodextrin (MβCD) and chlorpromazine enhanced surface localization of FGFR1 in PC12 cells and DRG neurons. Furthermore, MβCD and chlorpromazine increased FGF-2-induced neurite outgrowth of PC12 cells and axonal branching of adult DRG neurons overexpressing FGFR1, whereas MβCD inhibited FGF-2-induced axonal elongation. Analysis of the signaling pathways involved in axon morphology revealed that FGF-2-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was increased by inhibition of FGFR1 endocytosis. Together, our results imply that inhibition of FGFR1 endocytosis by MβCD or chlorpromazine promotes FGF-2-induced axonal branching. The results of this study confirm that internalization of FGFR1 controls axon growth and morphology of adult sensory neurons via selective activation of intracellular signaling pathways.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Axons
- Blotting, Western
- Chlorpromazine
- Dopamine Antagonists
- Endocytosis
- Ganglia, Spinal
- In Situ Nick-End Labeling
- Microscopy, Confocal
- Neurogenesis
- PC12 Cells
- Rats
- Receptor, Fibroblast Growth Factor, Type 1
- Sensory Receptor Cells
- Signal Transduction
- beta-Cyclodextrins
It is largely accepted that neurogenesis in the adult brain decreases with age and reduced levels of local neurotrophic support is speculated to be a contributing factor. Among neurotrophic factors involved on neurogenesis, we focused our attention on the neurotrophic system fibroblast growth factor-2 (FGF-2) and its receptor FGFR1, a potent modulator of precursor cell proliferation. In the present work, we aimed to analyse if potential age-dependent changes of the FGF-2/FGFR1 neurotrophic system may give account for the age-dependent decline of precursor cell proliferation in the neurogenic region of the subventricular zone (SVZ) in the rat brain. Using in situ hybridization and western blotting procedures we examined FGF-2 and FGFR1 expression levels in the SVZ of 20-month-old rats as compared to young adult 3-month-old rats. The results showed that during aging the FGF-2 and its receptor expression levels, both as mRNA and protein, were unchanged in the SVZ. The levels of phosphorylated FGFR1 form did not show significant variations suggesting that also the level of receptor activation does not change during aging. No changes were also observed in the phosphorylation of two FGFR1 related proteins involved in intracellular signaling, the canonical extracellular signal-regulated kinase Erk1/2 and the phospholipase-Cγ1. Additionally, we could show that also the proliferation rate of stem cells does not change during aging. Taken together, our results show that FGF-2/FGFR1 neurotrophic system expression level and its basal activation do not account for the age-dependent decline of precursor cell proliferation in the rat brain.
MeSH Terms
- Adult Stem Cells
- Aging
- Animals
- Brain
- Bromodeoxyuridine
- Cell Proliferation
- Cerebral Ventricles
- Fibroblast Growth Factor 1
- Fibroblast Growth Factor 2
- Gene Expression Regulation
- Male
- Mitogen-Activated Protein Kinase 3
- Neurogenesis
- Phospholipase C gamma
- Phosphorylation
- RNA, Messenger
- Rats
- Rats, Wistar
- Receptor, Fibroblast Growth Factor, Type 1
We explored the effect of single-nucleotide polymorphisms (SNPs) in the fibroblast growth factor 20 gene (FGF20) associated with risk for Parkinson's disease on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237; 116 men; 18-87 years). We analyzed high-resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in postmortem human brain tissue to determine the molecular correlates of these SNPs (N = 108; 72 men; 18-74 years). We found that the T allele carriers of rs12720208 in the 3'-untranslated region had relatively larger hippocampal volume (p = 0.0059) and diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal aging (p = 0.026). In postmortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGFR1 (FGF receptor 1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with aging, confirm a role of FGF20 in human brain structure and function during development and aging.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Cognition
- Female
- Fibroblast Growth Factors
- Genotype
- Hippocampus
- Humans
- Male
- MicroRNAs
- Middle Aged
- Organ Size
- Polymorphism, Single Nucleotide
- RNA, Messenger
- Receptor, Fibroblast Growth Factor, Type 1
- Young Adult
Precursor cell proliferation is present in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus of adult rat and persists during aging although at reduced levels. Previous studies have shown that acute intermittent nicotine treatment significantly increases fibroblast growth factor-2 (FGF-2) expression in several brain regions of aged rats. The aim of the present investigation was to test the hypothesis that nicotine-induced expression of FGF-2 may restore the age-related decline of precursor cell proliferation. It was first demonstrated that nicotine treatment increases both mRNA and protein FGF-2 in the SVZ of aged male rats (18 months old). The effect of nicotine on precursor cell proliferation in the SVZ was studied by i.p. injection of 5-bromo-2'-deoxyuridine (BrdU) 40 mg/kg to label dividing cells. The nicotine treatment was found to significantly enhance precursor cell proliferation in the SVZ. This increase was sufficiently large to restore the age-related decline of proliferating precursor cells observed in aged rats to that found in young adult rats (3 months old). FGF-2 was expressed in GFAP-positive cells and may act via its receptor FGFR1 that was found expressed in nestin-positive cells of the SVZ. The data obtained demonstrated that the age-related decline of precursor cell proliferation may be counteracted by activating a trophic mechanism mediated by FGF-2.
MeSH Terms
- Adult Stem Cells
- Aging
- Analysis of Variance
- Animals
- Antibodies
- Brain
- Bromodeoxyuridine
- Cell Count
- Cell Proliferation
- Fibroblast Growth Factor 2
- Gene Expression Regulation
- Glial Fibrillary Acidic Protein
- Intermediate Filament Proteins
- Lateral Ventricles
- Male
- Nerve Tissue Proteins
- Nestin
- Nicotine
- Nicotinic Agonists
- Rats
- Rats, Wistar
The highly ordered process of wound healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors. Consequently, the slowing of wound healing that occurs in the aged may be related to changes in the activity of these various regulatory factors. To gain additional insight into these issues, we quantified the absolute copy numbers of mRNAs encoding all the fibroblast growth factors (FGFs), their receptors (FGFRs) and two other growth factors in the dorsal skin of young and aged mice during the healing of full-thickness skin excisional wounds. In young adult mice (8 weeks old), FGF7, FGF10 and FGF22 mRNAs were all strongly expressed in healthy skin, and levels of FGF7 and 10 but not 22 increased 2- to 3.5-fold over differing time courses after wounding. The levels of FGF9, 16, 18 and especially 23 mRNAs were moderate or low in healthy skin but increased 2- to 33-fold after wounding. Among the four FGFRs, expression of only FGFR1 mRNA was augmented during wound healing. Expression of transforming growth factor-beta and hepatocyte growth factor was also high in healthy skin and was upregulated during healing. Notably, in aged mice (35 weeks old), where healing proceeded more slowly than in the young, both the basal and wound-induced mRNA expression of most of these genes was reduced. While these results confirm the established notion that FGFR2 IIIB ligands (FGF7 and FGF10) are important for wound healing, they also suggest that decreased expression of multiple FGF ligands contributes to the slowing of wound healing in aged mice and indicate the potential importance of further study of the involvement of FGF9, 16, 18 and 23 in the wound healing process.
MeSH Terms
- Actins
- Aging
- Animals
- Fibroblast Growth Factors
- Gene Expression
- Glyceraldehyde-3-Phosphate Dehydrogenases
- Hepatocyte Growth Factor
- Male
- Mice
- Mice, Mutant Strains
- RNA, Messenger
- Receptors, Fibroblast Growth Factor
- Skin
- Transforming Growth Factor beta
- Wound Healing
Heterogeneous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause a range of craniosynostosis syndromes. The specificity of the Apert syndrome-affected cranial phenotype reflects its narrow mutational range: 98% of cases of Apert syndrome result from an Ser252Trp or Pro253Arg mutation in the immunoglobulin-like (Ig)IIIa extracellular subdomain of FGFR2. In contrast, a broad range of mutations throughout the extracellular domain of FGFR2 causes the overlapping cranial phenotypes of Pfeiffer and Crouzon syndromes and related craniofacial dysostoses. In this paper the expression of FGFR1, the IgIIIa/c and IgIIIa/b isoforms of FGFR2, and FGFR3 is investigated in Apert syndrome (P253R mutation)- and Pfeiffer syndrome (C278F mutation)-affected fetal cranial tissue and is contrasted with healthy human control tissues. Both FGFR1 and FGFR3 are normally expressed in the differentiated osteoblasts of the periosteum and osteoid, in domains overlapped by that of FGFR2, which widely include preosseous cranial mesenchyme. Expression of FGFR2, however, is restricted to domains of advanced osseous differentiation in both Apert syndrome- and Pfeiffer syndrome-affected cranial skeletogenesis in the presence of fibroblast growth factor (FGF)2, but not in the presence of FGF4 or FGF7. Whereas expression of the FGFR2-IgIIIa/b (KGFR) isoform is restricted in normal human cranial osteogenesis, there is preliminary evidence that KGFR is ectopically expressed in Pfeiffer syndrome-affected cranial osteogenesis. Contraction of the FGFR2-IgIIIa/c (BEK) expression domain in cases of Apert syndrome- and Pfeiffer syndrome-affected fetal cranial ossification suggests that the mutant activation of this receptor, by ligand-dependent or ligand-independent means, results in negative autoregulation. This phenomenon, resulting from different mechanisms in the two syndromes, offers a model by which to explain differences in their cranial phenotypes.
MeSH Terms
- Acrocephalosyndactylia
- Aging
- Embryonic and Fetal Development
- Fetus
- Homeostasis
- Humans
- Infant
- Mutation
- Osteogenesis
- Phenotype
- Receptor Protein-Tyrosine Kinases
- Receptor, Fibroblast Growth Factor, Type 1
- Receptor, Fibroblast Growth Factor, Type 2
- Receptors, Fibroblast Growth Factor
- Skull
Fibroblast growth factor (FGF) signalling has been implicated in patterning, proliferation and cell differentiation in many organs, including the developing pancreas. Here we show that the FGF receptors (FGFRs) 1 and 2, together with the ligands FGF1, FGF2, FGF4, FGF5, FGF7 and [[FGF10]], are expressed in adult mouse beta-cells, indicating that FGF signalling may have a role in differentiated beta-cells. When we perturbed signalling by expressing dominant-negative forms of the receptors, FGFR1c and FGFR2b, in the pancreas, we found that that mice with attenuated FGFR1c signalling, but not those with reduced FGFR2b signalling, develop diabetes with age and exhibit a decreased number of beta-cells, impaired expression of glucose transporter 2 and increased proinsulin content in beta-cells owing to impaired expression of prohormone convertases 1/3 and 2. These defects are all characteristic of patients with type-2 diabetes. Mutations in the homeobox gene Ipf1/Pdx1 are linked to diabetes in both mouse and human. We also show that Ipf1/Pdx1 is required for the expression of FGFR1 signalling components in beta-cells, indicating that Ipf1/Pdx1 acts upstream of FGFR1 signalling in beta-cells to maintain proper glucose sensing, insulin processing and glucose homeostasis.
MeSH Terms
- Aging
- Animals
- Blood Glucose
- Diabetes Mellitus, Experimental
- Diabetes Mellitus, Type 2
- Fibroblast Growth Factors
- Glucose Transporter Type 1
- Glucose Transporter Type 2
- Homeodomain Proteins
- Humans
- Insulin
- Islets of Langerhans
- Mice
- Mice, Transgenic
- Monosaccharide Transport Proteins
- Pancreas
- Receptor Protein-Tyrosine Kinases
- Receptor, Fibroblast Growth Factor, Type 1
- Receptor, Fibroblast Growth Factor, Type 2
- Receptors, Fibroblast Growth Factor
- Signal Transduction
- Trans-Activators
Regional and temporal patterns of the expression of basic fibroblast growth factor (bFGF), and two of its high affinity receptors (FGFR1 and FGFR2), were examined in the male rat brain during early postnatal development; the reverse transcription-polymerase chain reaction (RT-PCR) was used to obtain mRNA measurements which were expressed relative to mRNA for GAPDH as a constant. In the rat cerebrum, the mRNAs for bFGF and for FGFR2 were relatively low in amount within the first postnatal week, but by 28 days, they were as high as in the 1-year-old rat cerebrum. In contrast, the expression of FGFR1 was biphasic: mRNA levels were higher at postnatal days 1 and 28 than at day 21. Quantitation of mRNA from microdissected regions of 28-day-old rat brain revealed that the expression of bFGF and of FGFR2 showed a marked variation between regions but the expression of FGFR1 appeared less variable between the regions that were analyzed. For all three genes the hippocampus appeared to have high relative amounts of mRNA. The temporal patterns of expression of bFGF, FGFR1 and FGFR2 also differed with brain region during early postnatal development. In the occipital cortex and inferior colliculus, the mRNAs for bFGF and FGFR2 both increased in amount during the first month, unlike that for FGFR1. However, in the cerebellum, the highest expression of bFGF and FGFR1 mRNAs occurred at postnatal day 1; FGFR2 expression apparently showed less change with age. The temporal changes in bFGF, FGFR1 and FGFR2 expression in different brain regions during early postnatal development suggest that receptor regulation may permit different physiological effects of bFGF according to brain region and developmental age.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Base Sequence
- Brain
- Cerebellum
- Fibroblast Growth Factor 2
- Gene Expression
- Hippocampus
- Inferior Colliculi
- Male
- Meninges
- Molecular Sequence Data
- Occipital Lobe
- Polymerase Chain Reaction
- RNA, Messenger
- RNA-Directed DNA Polymerase
- Rats
- Rats, Sprague-Dawley
- Receptors, Fibroblast Growth Factor
- Tissue Distribution