scholarly journals Microglial CX3CR1I249/M280 variant limits neurogenesis and remyelination in cuprizone-induced multiple sclerosis model

2021 ◽  
Author(s):  
Andrew S Mendiola ◽  
Kaira A Church ◽  
Sandra M Cardona ◽  
Difernando Vanegas ◽  
Shannon A Garcia ◽  
...  

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 regulates the activation of pathogenic microglia in models of MS and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280) variant increases MS disease progression. However, the role of hCX3CR1I249/M280 on microglial activation and central nervous system repair and regenerative mechanisms remain unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to remyelination and neurogenesis in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1I249/M280 exhibit marked demyelination and microgliosis follow acute cuprizone treatment. Cuprizone-treated CX3CR1-deficient and fractalkine-deficient mice displayed a comparable phenotype. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1I249/M280 upregulates genes associated with inflammation, oxidative stress and disease-associated microglia. In addition, gene expression analysis in the subgranular zone (SGZ) of the hippocampus in hCX3CR1I249/M280 mice was associated with a significant downregulation of gene networks linked to neurogenesis following acute demyelination. Confocal microscopy showed that hCX3CR1I249/M280 or loss of CX3CR1 signaling inhibits the generation of progeny from the neurogenic niche, including cells involved in myelin repair. These results provide evidence for the pathogenic capacity of hCX3CR1I249/M280 on microglia dysfunction and therapeutic targeting of CX3CR1 to promote CNS repair in MS.

2016 ◽  
Vol 24 (1-2) ◽  
pp. 33-38 ◽  
Author(s):  
Mohammad Taheri ◽  
Shirin Nemati ◽  
Abolfazl Movafagh ◽  
Mohammad Saberi ◽  
Reza Mirfakhraie ◽  
...  

2005 ◽  
Vol 441 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Paul Gallagher ◽  
Yongde Bao ◽  
Solange M.T. Serrano ◽  
Gavin D. Laing ◽  
R. David G. Theakston ◽  
...  

2018 ◽  
pp. 247-252 ◽  
Author(s):  
H. Nariyama ◽  
Y. Sugiyama ◽  
T. Shibuya ◽  
K. Hayashi ◽  
Y. Kanayama

2021 ◽  
Vol 33 (2) ◽  
pp. 108
Author(s):  
E. R. Maylem ◽  
L. Spicer ◽  
E. Atabay ◽  
E. Atabay ◽  
I. Batalha ◽  
...  

Fibrillin-1 (FBN1) functions as a structural protein in the ovary, whereas the role of its protein product asprosin remains unknown. Both proteins are encoded by the FBN1 gene; when it is cleaved at the C-terminal end, asprosin is produced. Asprosin acts as an orexigenic hormone and is associated with various metabolic parameters and sex related hormones in women. One goal of this research was to quantify FBN1 and the presumed asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1) mRNA in water buffalo granulosa cells (GC) and correlate them to aromatase (CYP19A1) gene expression. A second goal was to determine the effect of asprosin on follicular growth invivo. In Experiment 1, ovaries were collected from a local slaughterhouse, GC from small (<6mm) and large (6–13mm) follicles were aspirated, RNA was extracted, and gene expression analysis conducted. In Experiment 2, an intrafollicular injection of asprosin (6μL of asprosin in 194μL of phosphate-buffered saline; to achieve 20ng mL−1) or vehicle (200μL of phosphate-buffered saline; Controls) was given via the ovarian stroma below the dominant follicle of synchronized cows (n=5/group) 1 day after injection of prostaglandin F2α, and follicle sizes were measured daily via transrectal ultrasonography until the day of ovulation. Means were compared using t-test for gene expression analysis, and Pearson correlation coefficients calculated among FBN1, OR4M1, and CYP19A1 gene expression. A repeated-measures ANOVA was used to determine the effect of asprosin on follicle size and growth rate of follicles. In Experiment 1, FBN1 mRNA abundance was 7.51-fold greater in GC of small than large follicles (P<0.05). There was no significant difference in the OR4M1 (57.83±39.89 vs. 38.98±4.86) or CYP19A1 (11.46±3.72 vs. 8.27±4.81) mRNA abundance between the 2 sizes of follicles (P>0.10). Abundance of CYP19A1 mRNA was positively correlated with FBN1 (r=0.55, P<0.05) and OR4M1 mRNA (r=0.50, P<0.05). In Experiment 2, there was a treatment×day interaction (P<0.10) for follicle size and growth rate of follicles. Cows treated with asprosin had a higher growth rate from Day 1 to 2 (1.09±0.39 to 2.37±0.32 mm/day) than placebo cows (1.74±0.55 to 1.05±0.61 mm/day) after injection. Most of the follicles from both treatment groups ovulated 3 days post injection. These findings suggest that FBN1 (and thus asprosin) are present in buffalo GC and may be developmentally expressed. Also, asprosin may induce follicular growth when given invivo. Whether these proteins directly regulate aromatase expression, and therefore oestradiol production, during follicle development will require further study.


2008 ◽  
Vol 31 (11) ◽  
pp. 1620-1633 ◽  
Author(s):  
LAURA HUERTA ◽  
JAVIER FORMENT ◽  
JOSÉ GADEA ◽  
CARMEN FAGOAGA ◽  
LEANDRO PEÑA ◽  
...  

Neuroscience ◽  
2008 ◽  
Vol 154 (4) ◽  
pp. 1398-1407 ◽  
Author(s):  
B. Krischek ◽  
H. Kasuya ◽  
A. Tajima ◽  
H. Akagawa ◽  
T. Sasaki ◽  
...  

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