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

Shin J, Shin Y, Oh SM, Yang H, Yu WJ, Lee JP, Huh SO, Lee SH, Suh YH, Chung S, Kim HS - Cell Death Dis (2014)

Bottom Line: 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.Furthermore, our in vivo results showed that inhibition of miR-29b by in utero electroporation induced a profound defect in corticogenesis during mouse development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehakro, Jongro-gu, Seoul 110-799, South Korea.

ABSTRACT
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)-3β 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.

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A schematic representation of Wnt/β-catenin-mediated neurogenesis in the CNS of prenatal mammals. A putative schematic model of ICAT-dependent neurogenesis showing that miR-29b targets ICAT, thereby facilitating proliferation of neural stem cells in the developing brain
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fig5: A schematic representation of Wnt/β-catenin-mediated neurogenesis in the CNS of prenatal mammals. A putative schematic model of ICAT-dependent neurogenesis showing that miR-29b targets ICAT, thereby facilitating proliferation of neural stem cells in the developing brain

Mentions: The molecular aspects of the downstream components of β-catenin signaling have not been well characterized. Given that (1) miRNA-29 family members bind directly to ICAT, (2) β-catenin that is not bound to ICAT translocates to the nucleus, and (3) anti-miR-29b alters the functional properties of ICAT, it seems likely that ICAT is a component of β-catenin signal pathways (Figure 5). Although the genetic targets regulated by β-catenin and ICAT remain to be defined, our data provide a link between regulation of ICAT by miR-29b and corticogenesis. Furthermore, these results may contribute to a better understanding of the role of miR-29 miRNAs in the progression of many types of cancer, especially brain cancer. The miRNA molecules might also be considered as putative therapeutics in human patients with malignant glioblastoma multiforme (GBM), the most common type of primary brain tumor.


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

Shin J, Shin Y, Oh SM, Yang H, Yu WJ, Lee JP, Huh SO, Lee SH, Suh YH, Chung S, Kim HS - Cell Death Dis (2014)

A schematic representation of Wnt/β-catenin-mediated neurogenesis in the CNS of prenatal mammals. A putative schematic model of ICAT-dependent neurogenesis showing that miR-29b targets ICAT, thereby facilitating proliferation of neural stem cells in the developing brain
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4237260&req=5

fig5: A schematic representation of Wnt/β-catenin-mediated neurogenesis in the CNS of prenatal mammals. A putative schematic model of ICAT-dependent neurogenesis showing that miR-29b targets ICAT, thereby facilitating proliferation of neural stem cells in the developing brain
Mentions: The molecular aspects of the downstream components of β-catenin signaling have not been well characterized. Given that (1) miRNA-29 family members bind directly to ICAT, (2) β-catenin that is not bound to ICAT translocates to the nucleus, and (3) anti-miR-29b alters the functional properties of ICAT, it seems likely that ICAT is a component of β-catenin signal pathways (Figure 5). Although the genetic targets regulated by β-catenin and ICAT remain to be defined, our data provide a link between regulation of ICAT by miR-29b and corticogenesis. Furthermore, these results may contribute to a better understanding of the role of miR-29 miRNAs in the progression of many types of cancer, especially brain cancer. The miRNA molecules might also be considered as putative therapeutics in human patients with malignant glioblastoma multiforme (GBM), the most common type of primary brain tumor.

Bottom Line: 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.Furthermore, our in vivo results showed that inhibition of miR-29b by in utero electroporation induced a profound defect in corticogenesis during mouse development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehakro, Jongro-gu, Seoul 110-799, South Korea.

ABSTRACT
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)-3β 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.

Show MeSH