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Functional connection between fetal brain development and longevity in mice

ABSTRACT: The objective of the present study is to investigate gene regulation in developing fetal brain in congenic or inbred mice strains that differ in longevity. Gene expression and alternative splice variants were analyzed in a genome-wide manner in the fetal brain of C57BL/6J mice (long-lived), and compared to that of a congenic strain (short-lived) or an inbred strain AKR/J (short-lived) on days 12, 15 and 17 of gestation. The analysis showed a contrasting gene expression pattern during fetal brain development in these mice. Genes related to brain development, aging and spliceosome were significantly differentially regulated in the fetal brain of the short-lived mice when brain developed from d15 to d17. A significantly reduced number of splice variants were observed on d15 compared to d12 or d17 but in a strain-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE252079 | GEO | 2024/06/05

REPOSITORIES: GEO

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Project description:Differential gene expression between mouse distal chromsome 1 congenic and background and reciprocal congenic and background Genetic factors significantly affect vulnerability to alcohol dependence (alcoholism). We previously identified a quantitative trait locus on chromosome 1 (Adw1) with a large effect on predisposition to alcohol physiological dependence and associated withdrawal following both chronic and acute alcohol exposure in mice. We fine-mapped these loci to a 1.1-1.7 Mb interval syntenic with human 1q23.2-23.3. Adw1 interval genes show remarkable genetic variation among mice derived from the C57BL/6J and DBA/2J strains, the two most widely studied genetic animal models for alcohol-related traits. Here, we report the creation of a novel recombinant Adw1 congenic model (R2) in which the Adw1 interval from a donor C57BL/6J strain is introgressed onto a uniform, inbred DBA/2J genetic background. As expected, R2 mice demonstrate significantly less severe alcohol withdrawal compared to wild-type littermates. Additionally, comparing R2 and background strain animals, as well as reciprocal congenic (R8) and appropriate background strain animals, we assessed Adw1 dependent brain gene expression using microarray and quantitative PCR analyses. To our knowledge this includes the first Weighted Gene Co-expression Network Analysis using reciprocal congenic models. Importantly, this allows detection of co-expression patterns limited to one or common to both genetic backgrounds with high and low predisposition to alcohol withdrawal severity. The gene expression patterns (modules) in common contain genes related to oxidative phosphorylation, building upon human and animal model studies that implicate involvement of oxidative phosphorylation in alcohol use disorders. Finally, we demonstrate that administration of N-acetylcysteine, an FDA-approved antioxidant, significantly reduces symptoms of alcohol withdrawal (convulsions) in mice, thus validating a phenotypic role for this network. Taken together, these studies support the importance of mitochondrial oxidative homeostasis in alcohol withdrawal and identify this network as a valuable therapeutic target in human alcohol use disorders.

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Functional connection between fetal brain development and longevity in mice

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