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.

成年海马神经发生对健康大脑的学习与记忆功能具有重要贡献，且在代谢性与神经退行性疾病中出现失调，但目前关于神经干细胞活性、成年神经发生与整体代谢之间的分子关联仍尚未明确。我们采用无偏倚系统遗传学方法，在由自发性高血压（spontaneously hypertensive, SHR/OlaIpcv）大鼠与Brown Norway（BN-Lx/Cub）大鼠杂交培育的30个HXB/BXH重组近交系（recombinant inbred, RI）大鼠组成的遗传参考群体中，揭示了成年神经发生与外周组织代谢之间的遗传相关性。我们测定了该群体及亲代大鼠海马中的前体细胞增殖速率、新生神经元存活率，并结合已发表的代谢表型数据，鉴定出一个与血清葡萄糖水平及神经元存活率相关的“神经-代谢”数量性状位点（quantitative trait locus, QTL），并将其精细定位至Tti2（端粒2相互作用蛋白2，Telo2 interacting protein 2）基因——该基因是PIKK激酶活性与稳定性的调控因子。为验证Tti2作为该因果QTL基因的功能，我们在SHR/OlaIpcv遗传背景下构建了靶向移码突变的Tti2敲除模型。与野生型同窝对照相比，杂合子SHR-Tti2+/-大鼠表现出海马神经发生水平降低及糖代谢异常的特征。本数据集包含自发性高血压大鼠遗传背景下，6只野生型（SHR/OlaIpcv-Tti2+/+）与6只杂合子Tti2敲除（SHR/OlaIpcv-Tti2+/-）大鼠的海马、肝脏、比目鱼肌与腹膜脂肪组织的基因表达谱。整体实验设计：对上述遗传背景下的野生型与杂合子Tti2敲除大鼠的4种组织（腹膜脂肪、海马、肝脏、比目鱼肌）进行RNA测序（RNA-Seq）基因表达谱分析。每类组织选取RNA质量最优（RIN值最高）的5个样本进行测序。我们的研究结果提示，Tti2或可作为葡萄糖代谢与大脑结构可塑性之间的直接分子桥梁。