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000163944 1001_ $$0P:(DE-2719)9002273$$aSenko, Anna N$$b0$$eFirst author$$udzne
000163944 245__ $$aSystems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.
000163944 260__ $$aSan Francisco, Calif.$$bPublic Library of Science$$c2022
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000163944 520__ $$aNeurogenesis 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.
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000163944 650_7 $$0IY9XDZ35W2$$2NLM Chemicals$$aGlucose
000163944 650_2 $$2MeSH$$aAnimals
000163944 650_2 $$2MeSH$$aGlucose: genetics
000163944 650_2 $$2MeSH$$aGlucose: metabolism
000163944 650_2 $$2MeSH$$aHippocampus: metabolism
000163944 650_2 $$2MeSH$$aHumans
000163944 650_2 $$2MeSH$$aNeurogenesis: genetics
000163944 650_2 $$2MeSH$$aPhenotype
000163944 650_2 $$2MeSH$$aRats
000163944 650_2 $$2MeSH$$aRats, Inbred BN
000163944 650_2 $$2MeSH$$aRats, Inbred SHR
000163944 7001_ $$0P:(DE-2719)2812530$$aOverall, Rupert$$b1
000163944 7001_ $$aSilhavy, Jan$$b2
000163944 7001_ $$00000-0002-4218-8983$$aMlejnek, Petr$$b3
000163944 7001_ $$00000-0002-9076-3399$$aMalínská, Hana$$b4
000163944 7001_ $$00000-0002-2484-3630$$aHüttl, Martina$$b5
000163944 7001_ $$aMarková, Irena$$b6
000163944 7001_ $$0P:(DE-2719)2000006$$aFabel, Klaus S$$b7
000163944 7001_ $$00000-0002-6174-3209$$aLu, Lu$$b8
000163944 7001_ $$aStuchlik, Ales$$b9
000163944 7001_ $$00000-0001-8924-4447$$aWilliams, Robert W$$b10
000163944 7001_ $$aPravenec, Michal$$b11
000163944 7001_ $$0P:(DE-2719)2000011$$aKempermann, Gerd$$b12$$eLast author
000163944 773__ $$0PERI:(DE-600)2186725-2$$a10.1371/journal.pgen.1009638$$gVol. 18, no. 4, p. e1009638 -$$n4$$pe1009638$$tPLoS Genetics$$v18$$x1553-7390$$y2022
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