Chhabra Nirav Florian, Amarie Oana Veronica, Wu Moya, Amend Anna-Lena, Rubey Marina, Gradinger Daniel, Irmler Martin, Beckers Johannes, Rathkolb Birgit, Wolf Eckhard, Feuchtinger Annette, Huypens Peter, Teperino Raffaele, Rozman Jan, Przemeck Gerhard K H, Hrabě de Angelis Martin
Helmholtz Zentrum München, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Commun Biol. 2020 Oct 30;3(1):628. doi: 10.1038/s42003-020-01337-x.
The transcription factor PAX6 is involved in the development of the eye and pancreatic islets, besides being associated with sleep-wake cycles. Here, we investigated a point mutation in the RED subdomain of PAX6, previously described in a human patient, to present a comprehensive study of a homozygous Pax6 mutation in the context of adult mammalian metabolism and circadian rhythm. Pax6 mice lack appropriate retinal structures for light perception and do not display normal daily rhythmic changes in energy metabolism. Despite β cell dysfunction and decreased insulin secretion, mutant mice have normal glucose tolerance. This is associated with reduced hepatic glucose production possibly due to altered circadian variation in expression of clock and metabolic genes, thereby evading hyperglycemia. Hence, our findings show that while the RED subdomain is important for β cell functional maturity, the Leca2 mutation impacts peripheral metabolism via loss of circadian rhythm, thus revealing pleiotropic effects of PAX6.
转录因子PAX6除了与睡眠-觉醒周期有关外,还参与眼睛和胰岛的发育。在此,我们研究了PAX6红色亚结构域中的一个点突变(该突变先前在一名人类患者中被描述),以在成年哺乳动物新陈代谢和昼夜节律的背景下,对纯合Pax6突变进行全面研究。Pax6小鼠缺乏用于光感知的合适视网膜结构并且在能量代谢方面未表现出正常的每日节律变化。尽管存在β细胞功能障碍和胰岛素分泌减少的情况,但突变小鼠具有正常的葡萄糖耐量。这可能与肝脏葡萄糖生成减少有关,这可能是由于生物钟和代谢基因表达的昼夜变化改变所致,从而避免了高血糖症。因此,我们的研究结果表明,虽然红色亚结构域对β细胞功能成熟很重要,但Leca2突变通过昼夜节律丧失影响外周代谢,从而揭示了PAX6的多效性作用。