Department of Surgery, Weill Cornell Medical College, Cornell University, New York, United States.
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, United States.
Elife. 2017 Sep 28;6:e21992. doi: 10.7554/eLife.21992.
Sphingosine-1-phosphate (S1P) is generated through phosphorylation of sphingosine by sphingosine kinases (Sphk1 and Sphk2). We show that maternal-zygotic mutant zebrafish embryos () display early developmental phenotypes, including a delay in epiboly, depleted S1P levels, elevated levels of sphingosine, and resistance to sphingosine toxicity. The embryos also have strikingly increased levels of maternal transcripts encoding ceramide synthase 2b (Cers2b), and loss of Cers2b in embryos phenocopies sphingosine toxicity. An upstream region of the promoter supports enhanced expression of a reporter gene in embryos compared to wildtype embryos. Furthermore, ectopic expression of Cers2b protein itself reduces activity of the promoter, and this repression is relieved by exogenous sphingosine. Therefore, the genome recognizes the lack of sphingosine kinase activity and up-regulates as a salvage pathway for sphingosine turnover. Cers2b can also function as a sphingolipid-responsive factor to mediate at least part of a feedback regulatory mechanism.
鞘氨醇-1-磷酸（S1P）是通过鞘氨醇激酶（Sphk1 和 Sphk2）对鞘氨醇的磷酸化生成的。我们发现，母-合子突变体斑马鱼胚胎（）表现出早期发育表型，包括胚环延伸延迟、S1P 水平降低、鞘氨醇水平升高以及对鞘氨醇毒性的抗性。这些胚胎中也有显著增加的编码神经酰胺合酶 2b（Cers2b）的母体转录本水平，并且在 胚胎中缺失 Cers2b 可模拟鞘氨醇毒性。启动子的上游区域支持在与野生型胚胎相比， 胚胎中报告基因的表达增强。此外，Cers2b 蛋白本身的异位表达降低了启动子的活性，而外源性鞘氨醇可以缓解这种抑制。因此， 基因组识别出缺乏鞘氨醇激酶活性，并上调 作为鞘氨醇周转的补救途径。Cers2b 还可以作为一种鞘脂类反应因子，介导至少部分反馈调节机制。
