Makorin-2 is a neurogenesis inhibitor downstream of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signal
Makorin-2 is a neurogenesis inhibitor downstream of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signal
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DOI：
10.1074/jbc.m704768200
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发表时间：
2008-03-28
影响因子：
4.8
通讯作者：
Kung, Hsiang-Fu
中科院分区：
文献类型：
--
作者：
Yang, Pai-Hao;Cheung, William K. C.;Kung, Hsiang-Fu
Makorin-2属于Makorin环锌指基因家族，编码核糖核蛋白。在这里，我们克隆了非洲爪哇makorin-2(Mkrn2)基因，并研究了其在非洲爪哇神经发生中的作用。强制过表达mkrn2产生背后部缺陷和小头/短尾表型的蝌蚪，而mkrn2被吗啉反义寡核苷酸敲除则诱导蝌蚪双轴。在非洲爪哇动物帽子外植体实验中，mkrn2抑制激活素，维甲酸诱导动物帽子神经元化，这从PAN神经标记物神经细胞黏附分子的抑制中可见一斑。令人惊讶的是，mkrn2的抗神经发生活性不依赖于两个主要的神经发生信号级联，BMP-4和Wnt8通路。相反，mkrn2通过磷脂酰肌醇3-激酶(PI3K)和Akt介导的神经基因途径特异性地发挥作用。Mkrn2的过表达可完全阻断PI3K和Akt诱导的神经细胞黏附分子表达，但不能阻断GSK-3β诱导的神经细胞黏附分子表达，提示mkrn2作用于PI3K和Akt的下游和GSK-3β的上游。此外，mkrn2上调了GSK-3β的RNA和蛋白质水平。这些结果首次揭示了mkrn2在非洲爪哇胚胎发育过程中作为一个新的参与者在PI3K/Akt介导的神经发生中的重要作用。
Makorin-2 belongs to the makorin RING zinc finger gene family, which encodes putative ribonucleoproteins. Here we cloned the Xenopus makorin-2 (mkrn2) and characterized its function in Xenopus neurogenesis. Forced overexpression of mkrn2 produced tadpoles with dorso-posterior deficiencies and small-head/short-tail phenotype, whereas knockdown of mkrn2 by morpholino antisense oligonucleotides induced double axis in tadpoles. In Xenopus animal cap explant assay, mkrn2 inhibited activin, and retinoic acid induced animal cap neuralization, as evident from the suppression of a pan neural marker, neural cell adhesion molecule. Surprisingly, the anti-neurogenic activity of mkrn2 is independent of the two major neurogenesis signaling cascades, BMP-4 and Wnt8 pathways. Instead, mkrn2 works specifically through the phosphatidylinositol 3-kinase( PI3K) and Akt-mediated neurogenes is pathway. Overexpression of mkrn2 completely abrogated constitutively active PI3K-and Akt-induced, but not dominant negative glycogen synthase kinase-3 beta(GSK-3 beta)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3 beta. Moreover, mkrn2 up-regulated them RNA and protein levels of GSK-3 beta. These results revealed for the first time the important role of mkrn2 as a new player in PI3K/Akt-mediated neurogenesis during Xenopus embryonic development.