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The Mouse Hindbrain As a Model for Studying Embryonic Neurogenesis
Published on: January 29, 2018
MiR-29b controls fetal mouse neurogenesis by regulating ICAT-mediated Wnt/β-catenin signaling
1Department 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.
Insights
MicroRNA-29b (miR-29b) directly targets ICAT, regulating Wnt/β-catenin signaling. This microRNA is crucial for neural stem cell proliferation, differentiation, and proper fetal mouse brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Wnt/β-catenin signaling is vital for mammalian development and homeostasis.
- The precise roles of Wnt/β-catenin components in brain development are not fully understood.
- Glycogen synthase kinase (GSK)-3β inactivation leads to nuclear β-catenin accumulation, a process modulated by the inhibitor of β-catenin and T cell factor (ICAT).
Purpose of the Study:
- To investigate if microRNA-29 (miR-29) family members regulate ICAT during neurogenesis.
- To determine if ICAT deregulation by miR-29 impacts neurogenesis via β-catenin signaling.
- To elucidate the role of miR-29b in neural stem cell (NSC) function and corticogenesis.
Main Methods:
- Quantitative analysis of miR-29b and ICAT expression in cultured neural stem cells (NSCs).
- Luciferase reporter assays to confirm direct targeting of ICAT by miR-29b.
- In vitro experiments assessing NSC self-renewal, proliferation, and differentiation upon miR-29b treatment.
- In vivo studies using in utero electroporation to inhibit miR-29b in developing mouse embryos.
Main Results:
- miR-29b was significantly upregulated in cultured NSCs, correlating with decreased ICAT levels.
- miR-29b directly targets the 3'-UTR of ICAT, reducing its activity.
- miR-29b treatment inhibited NSC self-renewal and proliferation, influencing cell fate decisions.
- Inhibition of miR-29b in vivo resulted in severe defects in mouse corticogenesis.
Conclusions:
- miR-29b plays a critical role in fetal mouse neurogenesis.
- The mechanism involves the regulation of ICAT and subsequent modulation of Wnt/β-catenin signaling.
- miR-29b is essential for normal NSC behavior and the development of the cerebral cortex.
