GSE160361
System genetics in rat HXB/BXH reference population identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose
Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain and is dysregulated in metabolic and neurodegenerative diseases, but the molecular relationships between neural stem cells activity, adult neurogenesis and global metabolism are largely unknown. We applied unbiased systems genetics to reveal genetic correlations between adult neurogenesis and metabolism of peripheral tissues in a genetic reference population of 30 HXB/BXH recombinant inbred (RI) strains, derived from a cross between spontaneously hypertensive (SHR/OlaIpcv) and Brown Norway (BN-Lx/Cub) rats. We measured the rates of precursor cell proliferation, survival of new neurons, and gene expression profiles in the hippocampi of RI and parental strains and combined them with published metabolic phenotypes to reveal a “neuro-metabolic” quantitative trait locus (QTL) for serum glucose and neuronal survival, which was further narrowed down to the Tti2 (Telo2 interacting protein 2) gene, which is a regulator of activity and stability of PIKK kinases. To validate Tti2 as a causal QTL gene, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- rats showed decreased hippocampal neurogenesis and hallmarks of dysglycemia when compared to wild-type littermates. Here we present gene expression profiling of hippocampus, liver, soleus muscle and peritoneal fat in SHR-Tti2 heterozygous rats and wild-type SHR control littermates.  Our findings suggest that Tti2 may represent a direct molecular link between glucose metabolism and structural brain plasticity. Overall design: Gene expression profiling (RNA-Seq) of  multiple tissues (peritoneal fat, hippocampus, liver, soleus muscle) extracted from six wild type and six heterozygous Tti2 knock-out rats on the spontaneously hypertensive rat genetic background (SHR/OlaIpcv-Tti2+/+ and SHR/OlaIpcv-Tti2+/- respectively). For each tissue, five samples with the best RNA quality (the highest rin number) were sequenced.