% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Senko:163944,
      author       = {Senko, Anna N and Overall, Rupert and Silhavy, Jan and
                      Mlejnek, Petr and Malínská, Hana and Hüttl, Martina and
                      Marková, Irena and Fabel, Klaus S and Lu, Lu and Stuchlik,
                      Ales and Williams, Robert W and Pravenec, Michal and
                      Kempermann, Gerd},
      title        = {{S}ystems genetics in the rat {HXB}/{BXH} family identifies
                      {T}ti2 as a pleiotropic quantitative trait gene for adult
                      hippocampal neurogenesis and serum glucose.},
      journal      = {PLoS Genetics},
      volume       = {18},
      number       = {4},
      issn         = {1553-7390},
      address      = {San Francisco, Calif.},
      publisher    = {Public Library of Science},
      reportid     = {DZNE-2022-00618},
      pages        = {e1009638},
      year         = {2022},
      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.},
      keywords     = {Animals / Glucose: genetics / Glucose: metabolism /
                      Hippocampus: metabolism / Humans / Neurogenesis: genetics /
                      Phenotype / Rats / Rats, Inbred BN / Rats, Inbred SHR /
                      Glucose (NLM Chemicals)},
      cin          = {AG Kempermann / AG White},
      ddc          = {610},
      cid          = {I:(DE-2719)1710001 / I:(DE-2719)1740002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35377872},
      pmc          = {pmc:PMC9060359},
      doi          = {10.1371/journal.pgen.1009638},
      url          = {https://pub.dzne.de/record/163944},
}