Abstract
Although studies with inbred strains of mice have shown that infarct size is largely determined by the extent of collateral vessel connections between arteries in the brain that enable reperfusion of the ischemic territory, we have identified strain pairs that do not vary in this vascular phenotype, but which nonetheless exhibit large differences in infarct size. In this study we performed quantitative trait locus (QTL) mapping in mice from an intercross between two such strains, WSB/EiJ (WSB) and C57BL/6J (B6). This QTL mapping revealed only one neuroprotective locus on Chromosome 8 (Chr 8) that co-localizes with a neuroprotective locus we mapped previously from F2 progeny between C3H/HeJ (C3H) and B6. The allele-specific phenotypic effect on infarct volume at the genetic region identified by these two independent mappings was in the opposite direction of the parental strain phenotype; namely, the B6 allele conferred increased susceptibility to ischemic infarction. Through two reciprocal congenic mouse lines with either the C3H or B6 background at the Chr 8 locus, we verified the neuroprotective effects of this genetic region that modulates infarct volume without any effect on the collateral vasculature. Additionally, we surveyed non-synonymous coding SNPs and performed RNA-sequencing analysis to identify potential candidate genes within the genetic interval. Through these approaches, we suggest new genes for future mechanistic studies of infarction following ischemic stroke, which may represent novel gene/protein targets for therapeutic development.
Highlights
Ischemic stroke is caused by a disruption of the blood supply to the brain leading to neuronal cell death in the ischemic region
We generated reciprocal congenic mouse lines in order to evaluate the Civq4 quantitative trait locus (QTL) effect on both genetic backgrounds. (B6 × C3H) F1 animals were backcrossed to B6 to generate B6.C3HCivq4 congenics, which we refer to as LineB. (B6 × C3H) F1 animals were backcrossed to C3H to generate C3H.B6Civq4, which we refer to as LineC
We returned to our phenotypic characterization of the eight founder mouse strains of the collaborative cross (CC) (Lee et al, 2019) in order to identify strains that exhibited differences in infarct volume due to vascular-independent effects
Summary
Ischemic stroke is caused by a disruption of the blood supply to the brain leading to neuronal cell death in the ischemic region. In the United States, stroke is the fourth-leading cause of death with almost 800,000 new or recurrent cases occurring each year (Roger et al, 2012). Risk factors for stroke include environmental influences (e.g., smoking, diabetes, obesity, etc.), but epidemiologic studies have estimated that two-thirds of the risk for developing ischemic stroke is. GWAS for ischemic stroke, including a recent meta analysis, have identified dozens of variants in genes involved in diverse biological processes, and many of these variants share risk factors with other vascular traits or intermediate phenotypes of stroke (Malik et al, 2018). Pharmacological interventions to reduce stroke risk have focused on reducing these related vascular risk factors (Malik et al, 2018)
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