Makorin-2 is a neurogenesis inhibitor downstream of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signal.
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-3beta (GSK-3beta)-induced, neural cell adhesion molecule expression, indicating that mkrn2 acts downstream of PI3K and Akt and upstream of GSK-3beta. Moreover, mkrn2 up-regulated the mRNA and protein levels of GSK-3beta. 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.
Yang
Pai-Hao
PH
Joint State Key Laboratory in Oncology in South China, Sun Yat-Sen University, Guangzhou, China.
Cheung
William K C
WK
Peng
Ying
Y
He
Ming-Liang
ML
Wu
Guo-Qing
GQ
Xie
Dan
D
Jiang
Bing-Hua
BH
Huang
Qiu-Hua
QH
Chen
Zhu
Z
Lin
Marie C M
MC
Kung
Hsiang-Fu
HF
D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008969:Molecular Sequence Data; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
C528868:Mkrn2 protein, Xenopus; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3