Makorin-2 Is a Neurogenesis Inhibitor Downstream of Phosphatidylinositol 3-Kinase/Akt (PI3K/Akt) Signal

• Published in: The Journal of biological chemistry Vol. 283; no. 13; pp. 8486 - 8495
• Main Authors: Yang, Pai-Hao, Cheung, William K.C., Peng, Ying, He, Ming-Liang, Wu, Guo-Qing, Xie, Dan, Jiang, Bing-Hua, Huang, Qiu-Hua, Chen, Zhu, Lin, Marie C.M., Kung, Hsiang-Fu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Aging - physiology; Animals; Brain - metabolism; Cell Differentiation; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - embryology; Embryo, Nonmammalian - metabolism; Female; Gene Expression Regulation, Developmental; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Molecular Sequence Data; Neural Cell Adhesion Molecules - genetics; Neurons - cytology; Neurons - metabolism; Oocytes - metabolism; Phenotype; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleoproteins - genetics; Ribonucleoproteins - metabolism; RNA, Messenger - genetics; Signal Transduction; Skin - metabolism; Wnt Proteins - metabolism; Xenopus; Xenopus laevis - embryology; Xenopus laevis - genetics; Xenopus laevis - growth & development; Xenopus laevis - metabolism; Xenopus Proteins - genetics; Xenopus Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M704768200

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 neurogenesis pathway. Overexpression of mkrn2 completely abrogated constitutively active PI3K- and Akt-induced, but not dominant negative glycogen synthase kinase-3β (GSK-3β)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3β. Moreover, mkrn2 up-regulated the mRNA and protein levels of GSK-3β. 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.