Maternal and Zygotic Sphingosine Kinase 2 Are Indispensable for Cardiac Development in Zebrafish
Maternal and Zygotic Sphingosine Kinase 2 Are Indispensable for Cardiac Development in Zebrafish
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DOI：
10.1074/jbc.m114.634717
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发表时间：
2015-06-12
影响因子：
4.8
通讯作者：
Kawahara, Atsuo
中科院分区：
文献类型：
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作者：
Hisano, Yu;Inoue, Asuka;Kawahara, Atsuo
在无脊椎动物和脊椎动物中，鞘氨醇1-磷酸（S1 P）是由鞘氨醇通过鞘氨醇激酶（SPHK 1和SPHK 2）合成的，而S1 P的特异性受体（S1 PRs）选择性地出现在脊椎动物中，这表明S1 P在无脊椎动物中获得了新的功能。由于SPHK 1和SPHK 2的发育功能在脊椎动物中仍然不清楚，我们通过使用转录激活因子样效应物核酸酶在其编码区中引入过早终止密码子来产生SPHK 1或SPHK 2基因破坏的斑马鱼。合子型的sphk 1和sphk 2斑马鱼突变体均未表现出明显的发育缺陷，且均能生长至成年。母合子sphk 2突变体（MZsphk 2），而不是母合子sphk 1突变体和母sphk 2突变体，有缺陷的心脏祖细胞迁移和伴随的S1 P水平下降，导致两个心脏表型（心裂）。通过注射sphk 2 mRNA拯救的MZsphk 2中的心裂与S1 P转运蛋白spns 2和S1 P受体s1 pr 2的合子突变体的表型相同，表明Sphk 2-Spns 2-S1 pr 2轴调节斑马鱼的心脏祖细胞迁移。在脊椎动物器官发生过程中，母体提供的脂质介质的贡献是母合子Sphk 2的需要。
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 invertebrates. 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 grewtoadults. 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.