TY  - JOUR
AU  - Senko, Anna N
AU  - Overall, Rupert
AU  - Silhavy, Jan
AU  - Mlejnek, Petr
AU  - Malínská, Hana
AU  - Hüttl, Martina
AU  - Marková, Irena
AU  - Fabel, Klaus S
AU  - Lu, Lu
AU  - Stuchlik, Ales
AU  - Williams, Robert W
AU  - Pravenec, Michal
AU  - Kempermann, Gerd
TI  - Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.
JO  - PLoS Genetics
VL  - 18
IS  - 4
SN  - 1553-7390
CY  - San Francisco, Calif.
PB  - Public Library of Science
M1  - DZNE-2022-00618
SP  - e1009638
PY  - 2022
AB  - 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.
KW  - Animals
KW  - Glucose: genetics
KW  - Glucose: metabolism
KW  - Hippocampus: metabolism
KW  - Humans
KW  - Neurogenesis: genetics
KW  - Phenotype
KW  - Rats
KW  - Rats, Inbred BN
KW  - Rats, Inbred SHR
KW  - Glucose (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35377872
C2  - pmc:PMC9060359
DO  - DOI:10.1371/journal.pgen.1009638
UR  - https://pub.dzne.de/record/163944
ER  -