Department of Medical Genetics, Institute for Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK.
Mol Psychiatry. 2012 Mar;17(3):267-79. doi: 10.1038/mp.2011.73. Epub 2011 Jun 28.
The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients.
基本螺旋-环-螺旋 PAS（Per、Arnt、Sim）结构域转录因子基因 NPAS3 是精神疾病的复制遗传风险因素。敲除（KO）小鼠模型表现出与人类疾病一致的行为和成年神经发生缺陷。为了定义 NPAS3 发病机制的位置和机制，我们结合了免疫荧光、转录组学和代谢组学方法。在海马亚颗粒区——成年神经发生的部位——观察到强烈的 Npas3 免疫反应，但仅限于成熟而非增殖的神经元前体细胞。过表达 NPAS3 的 HEK293 细胞系的微阵列分析表明，转录靶标根据昼夜节律背景和 C 末端缺失而变化。NPAS3 上调最显著的靶基因 VGF 编码具有神经发生、抑郁和精神分裂症作用的分泌肽。VGF 只是许多 NPAS3 靶基因之一，也受转录因子 SOX 家族调节，表明在神经发育功能上存在重叠。NPAS3 对多个糖酵解基因的平行抑制揭示了其在调节葡萄糖代谢中的第二个作用。使用高分辨率质谱比较野生型和 Npas3 KO 代谢物组成证实了这些转录发现。KO 脑组织中 NAD(+)、糖酵解代谢物（如二羟丙酮磷酸和果糖-1,6-二磷酸）、戊糖磷酸途径成分和 Krebs 循环中间产物（琥珀酸和α-酮戊二酸）的水平明显改变。NPAS3 活性的双重神经发育和代谢方面增加了我们对精神疾病病因的理解，并可能为精神疾病患者中常见的先天和药物诱导的糖尿病易感性提供一种机制。
