In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 4 ( 2022-4-4), p. e1009638-
Abstract:
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN- Lx /Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1–66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene ( Tti2 )—a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2 , we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR- Tti2 +/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009638
DOI:
10.1371/journal.pgen.1009638.g001
DOI:
10.1371/journal.pgen.1009638.g002
DOI:
10.1371/journal.pgen.1009638.g003
DOI:
10.1371/journal.pgen.1009638.g004
DOI:
10.1371/journal.pgen.1009638.g005
DOI:
10.1371/journal.pgen.1009638.t001
DOI:
10.1371/journal.pgen.1009638.t002
DOI:
10.1371/journal.pgen.1009638.t003
DOI:
10.1371/journal.pgen.1009638.t004
DOI:
10.1371/journal.pgen.1009638.s001
DOI:
10.1371/journal.pgen.1009638.s002
DOI:
10.1371/journal.pgen.1009638.s003
DOI:
10.1371/journal.pgen.1009638.s004
DOI:
10.1371/journal.pgen.1009638.s005
DOI:
10.1371/journal.pgen.1009638.s006
DOI:
10.1371/journal.pgen.1009638.s007
DOI:
10.1371/journal.pgen.1009638.s008
DOI:
10.1371/journal.pgen.1009638.s009
DOI:
10.1371/journal.pgen.1009638.s010
DOI:
10.1371/journal.pgen.1009638.s011
DOI:
10.1371/journal.pgen.1009638.s012
DOI:
10.1371/journal.pgen.1009638.s013
DOI:
10.1371/journal.pgen.1009638.s014
DOI:
10.1371/journal.pgen.1009638.s015
DOI:
10.1371/journal.pgen.1009638.s016
DOI:
10.1371/journal.pgen.1009638.r001
DOI:
10.1371/journal.pgen.1009638.r002
DOI:
10.1371/journal.pgen.1009638.r003
DOI:
10.1371/journal.pgen.1009638.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2186725-2
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