Hisano Yu, Inoue Asuka, Okudaira Michiyo, Taimatsu Kiyohito, Matsumoto Hirotaka, Kotani Hirohito, Ohga Rie, Aoki Junken, Kawahara Atsuo
From the Laboratory for Developmental Gene Regulation, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198,
the Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, PRESTO and.
J Biol Chem. 2015 Jun 12;290(24):14841-51. doi: 10.1074/jbc.M114.634717. Epub 2015 Apr 23.
Sphingosine 1-phosphate (S1P) is synthesized from sphingosine by sphingosine kinases (SPHK1 and SPHK2) in invertebrates and vertebrates, whereas specific receptors for S1P (S1PRs) selectively appear in vertebrates, suggesting that S1P acquires novel functions in vertebrates. Because the developmental functions of SPHK1 and SPHK2 remain obscure in vertebrates, we generated sphk1 or sphk2 gene-disrupted zebrafish by introducing premature stop codons in their coding regions using transcription activator-like effector nucleases. Both zygotic sphk1 and sphk2 zebrafish mutants exhibited no obvious developmental defects and grew to adults. The maternal-zygotic sphk2 mutant (MZsphk2), but not the maternal-zygotic sphk1 mutant and maternal sphk2 mutant, had a defect in the cardiac progenitor migration and a concomitant decrease in S1P level, leading to a two-heart phenotype (cardia bifida). Cardia bifida in MZsphk2, which was rescued by injecting sphk2 mRNA, was a phenotype identical to that of zygotic mutants of the S1P transporter spns2 and S1P receptor s1pr2, indicating that the Sphk2-Spns2-S1pr2 axis regulates the cardiac progenitor migration in zebrafish. The contribution of maternally supplied lipid mediators during vertebrate organogenesis presents as a requirement for maternal-zygotic Sphk2.
鞘氨醇-1-磷酸(S1P)由鞘氨醇激酶(SPHK1和SPHK2)在无脊椎动物和脊椎动物中从鞘氨醇合成,而S1P的特异性受体(S1PRs)选择性地出现在脊椎动物中,这表明S1P在脊椎动物中获得了新功能。由于SPHK1和SPHK2在脊椎动物中的发育功能仍不清楚,我们通过使用转录激活样效应核酸酶在其编码区引入过早的终止密码子,生成了sphk1或sphk2基因敲除的斑马鱼。合子型sphk1和sphk2斑马鱼突变体均未表现出明显的发育缺陷,并成长为成体。母源合子型sphk2突变体(MZsphk2),而非母源合子型sphk1突变体和母源sphk2突变体,在心脏祖细胞迁移方面存在缺陷,同时S1P水平降低,导致双心表型(心脏裂)。通过注射sphk2 mRNA挽救的MZsphk2中的心脏裂,与S1P转运体spns2和S1P受体s1pr2的合子型突变体表型相同,表明Sphk2-Spns2-S1pr2轴调节斑马鱼心脏祖细胞的迁移。在脊椎动物器官发生过程中,母源提供的脂质介质的作用表现为对母源合子型Sphk2的需求。
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