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

Yusuf, Issa Olakunle; Cheng, Pei Hsun; Chen, Hsiu Mei; Chang, Yu Fan; Chang, Chin Sung; Yang, Han In; Lin, Chia Wei; Tsai, Shaw-Jenq; Chuang, Jih Ing; Wu, Chia Ching; Huang, Bu Miin; Sun, Hung-Yu; Yang, Shang Hsun

doi:10.1159/000491889

Cited by 19 publications

(18 citation statements)

References 42 publications

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“…4 a). Similarly, checking the (epi)genomic profiles at FGF9 locus, highly implicated in neuronal differentiation 36 , 37 showed the hypomethylation directly at the regulatory element targeting this gene, with significantly increased patterns of expression in the neuronal subtype (Fig. 4 b).…”

Section: Resultsmentioning

confidence: 83%

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Eray¹,

Güneri

Yılmaz³

et al. 2020

Sci Rep

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Urothelial carcinoma of the bladder is the most frequent bladder cancer affecting more than 400,000 people each year. Histopathologically, it is mainly characterized as muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC). Recently, the studies largely driven by consortiums such as TCGA identified the mutational landscape of both MIBC and NMIBC and determined the molecular subtypes of bladder cancer. Because of the exceptionally high rate of mutations in chromatin proteins, bladder cancer is thought to be a disease of chromatin, pointing out to the importance of studying epigenetic deregulation and the regulatory landscape of this cancer. In this study, we have analyzed ATAC-seq data generated for MIBC and integrated our findings with gene expression and DNA methylation data to identify subgroup specific regulatory patterns for MIBC. Our computational analysis revealed three MIBC regulatory clusters, which we named as neuronal, non-neuronal and luminal outlier. We have identified target genes of neuronal regulatory elements to be involved in WNT signaling, while target genes of non-neuronal and luminal outlier regulatory regions were enriched in epithelial differentiation and drug metabolism, respectively. Neuronal regulatory elements were determined to be ß-catenin targets (p value = 3.59e−08) consisting of genes involved in neurogenesis such as FGF9, and PROX1, and significantly enriched for TCF/LEF binding sites (p value = 1e−584). Our results showed upregulation of ß-catenin targets regulated by neuronal regulatory elements in three different cohorts, implicating ß-catenin signature in neuronal bladder cancer. Further, integration with mutation data revealed significantly higher oncogenic exon 3 ß-catenin mutations in neuronal bladder cancer compared to non-neuronal (odds ratio = 31.33, p value = 1.786e−05). Our results for the first time identify regulatory elements characterizing neuronal bladder cancer and links these neuronal regulatory elements with WNT signaling via mutations in β-catenin and its destruction complex components.

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Section: Resultsmentioning

confidence: 83%

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Eray¹,

Güneri

Yılmaz³

et al. 2020

Sci Rep

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“…In addition, FGF9 led to different protein expressions related to morphological and synaptic functions in the Q7 and Q111 cells (Figure 2 and 3). In several previous studies by different research groups, different responses induced by exogenous stimulations in Q7 and Q111 cells were shown [14,[51][52][53], suggesting these two cell lines have different regulatory networks to respond to exogenous stimulation. Since Q111 cells carry mutant HTT, which leads to disruption of gene regulation in HD models [3,54,55], Q111 cells may increase complementary gene regulation against HD.…”

Section: Discussionmentioning

confidence: 87%

“…Fibroblast growth factors (FGFs) influence neuronal morphology [8][9][10] and are involved in the pathogenesis of many neurodegenerative diseases [11][12][13]. Fibroblast growth factor 9 (FGF9), a specific type of FGF, has been reported to regulate neuronal development in vivo [10] and also has been suggested to provide neuroprotective functions in Parkinson's disease (PD) and Huntington's disease (HD), two important neurodegenerative diseases [13][14][15][16]. This suggests that FGF9 may be an exogenous candidate to intervene in these diseases through regulating neuronal morphology.…”

Section: Introductionmentioning

confidence: 99%

Fibroblast growth factor 9 stimulates neurite outgrowth through NF-kB signaling in striatal cell Huntington’s disease models

Yusuf

Chen

Cheng

et al. 2020

Preprint

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Proper development of neuronal cells is important for brain functions, and impairment of neuronal development may lead to neuronal disorders, implying that improvement in neuronal development may be a therapeutic direction for these diseases. Huntington’s disease (HD) is a neurodegenerative disease characterized by impairment of neuronal structures, ultimately leading to neuronal death and dysfunctions of the central nervous system. Based on previous studies, fibroblast growth factor 9 (FGF9) may provide neuroprotective functions in HD, and FGFs may enhance neuronal development and neurite outgrowth. However, whether FGF9 can provide neuronal protective functions through improvement of neuronal morphology in HD is still unclear. Here, we study the effects of FGF9 on neuronal morphology in HD and attempt to understand the related working mechanisms. Taking advantage of striatal cell lines from HD knock-in mice, we found that FGF9 increases neurite outgrowth and upregulates several structural and synaptic proteins under HD conditions. In addition, activation of nuclear factor kappa B (NF-kB) signaling by FGF9 was observed to be significant in HD cells, and blockage of NF-kB leads to suppression of these structural and synaptic proteins induced by FGF9, suggesting the involvement of NF-kB signaling in these effects of FGF9. Taken these results together, FGF9 may enhance neurite outgrowth through upregulation of NF-kB signaling, and this mechanism could serve as an important mechanism for neuroprotective functions of FGF9 in HD.

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“…Previously, we demonstrated that FGF9 protects striatal cells against cell death and oxidative stress in HD [14,15]. Since FGF9 has been reported to play a role in neuronal morphology in vivo [10], we were curious as to whether FGF9 would enhance neurite outgrowth and thus provide neuroprotective functions in HD cells.…”

Section: Fgf9 Increases Neuronal Neurite Outgrowth In Hd Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fibroblast Growth Factor 9 Stimulates Neuronal Length Through NF-kB Signaling in Striatal Cell Huntington’s Disease Models

et al. 2021

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Proper development of neuronal cells is important for brain functions, and impairment of neuronal development may lead to neuronal disorders, implying that improvement in neuronal development may be a therapeutic direction for these diseases. Huntington's disease (HD) is a neurodegenerative disease characterized by impairment of neuronal structures, ultimately leading to neuronal death and dysfunctions of the central nervous system. Based on previous studies, fibroblast growth factor 9 (FGF9) may provide neuroprotective functions in HD, and FGFs may enhance neuronal development and neurite outgrowth. However, whether FGF9 can provide neuronal protective functions through improvement of neuronal morphology in HD is still unclear. Here, we study the effects of FGF9 on neuronal morphology in HD and attempt to understand the related working mechanisms. Taking advantage of striatal cell lines from HD knock-in mice, we found that FGF9 increases neurite outgrowth and upregulates several structural and synaptic proteins under HD conditions. In addition, activation of nuclear factor kappa B (NF-kB) signaling by FGF9 was observed to be significant in HD cells, and blockage of NF-kB leads to suppression of these structural and synaptic proteins induced by FGF9, suggesting the involvement of NF-kB signaling in these effects of FGF9. Taken these results together, FGF9 may enhance neurite outgrowth through upregulation of NF-kB signaling, and this mechanism could serve as an important mechanism for neuroprotective functions of FGF9 in HD.

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

Cited by 19 publications

References 42 publications

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Analysis of open chromatin regions in bladder cancer links β-catenin mutations and Wnt signaling with neuronal subtype of bladder cancer

Fibroblast growth factor 9 stimulates neurite outgrowth through NF-kB signaling in striatal cell Huntington’s disease models

Fibroblast Growth Factor 9 Stimulates Neuronal Length Through NF-kB Signaling in Striatal Cell Huntington’s Disease Models

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