MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/β-catenin signaling

• Published in: Cell death & disease Vol. 5; no. 10; p. e1473
• Main Authors: Shin, J, Shin, Y, Oh, S-M, Yang, H, Yu, W-J, Lee, J-P, Huh, S-O, Lee, S H, Suh, Y-H, Chung, S, Kim, H-S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.10.2014; Nature Publishing Group
• Subjects: 13/51; 3' Untranslated Regions - genetics; 38/77; 38/89; 631/136/368; 631/337/384/331; 631/80/86; 64/60; 82/29; Animals; Antibodies; Base Sequence; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Brain - embryology; Brain - metabolism; Cell Biology; Cell Culture; Cell Cycle Proteins - metabolism; Cell Differentiation - genetics; Cell Nucleus - metabolism; Cell Proliferation; Cells, Cultured; Female; Fetus - metabolism; HEK293 Cells; Humans; Immunology; Life Sciences; Mice; MicroRNAs - metabolism; Models, Biological; Molecular Sequence Data; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis - genetics; Original; original-article; Rats; Repressor Proteins - metabolism; Up-Regulation - genetics; Wnt Signaling Pathway
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.439

β -Catenin has been widely implicated in the regulation of mammalian development and cellular homeostasis. However, the mechanisms by which Wnt/ β -catenin signaling components regulate physiological events during brain development remain undetermined. Inactivation of glycogen synthase kinase (GSK)-3 β leads to β -catenin accumulation in the nucleus, where it couples with T-cell factor (TCF), an association that is disrupted by ICAT (inhibitor of β -catenin and T cell factor). In this study, we sought to determine whether regulation of ICAT by members of the microRNA-29 family plays a role during neurogenesis and whether deregulation of ICAT results in defective neurogenesis due to impaired β -catenin-mediated signaling. We found that miR-29b, but not miR-29a or 29c, is significantly upregulated in three-dimensionally cultured neural stem cells (NSCs), whereas ICAT is reduced as aged. Treatment with a miR-29b reduced the reporter activity of a luciferase-ICAT 3′-UTR construct whereas a control (scrambled) miRNA oligonucleotide did not, indicating that miR-29b directly targets the 3′-UTR of ICAT. We also found that treatment with miR-29b diminished NSC self-renewal and proliferation, and controlled their fate, directing their differentiation along certain cell lineages. Furthermore, our in vivo results showed that inhibition of miR-29b by in utero electroporation induced a profound defect in corticogenesis during mouse development. Taken together, our results demonstrate that miR-29b plays a pivotal role in fetal mouse neurogenesis by regulating ICAT-mediated Wnt/ β -catenin signaling.