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Differentiation of a Human Neural Stem Cell Line on Three Dimensional Cultures, Analysis of MicroRNA and Putative Target Genes
Published on: April 12, 2015
MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells
Marijn Schouten1, Silvina A Fratantoni2, Chantal J Hubens3
1Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.
Abstract:
Adult neurogenesis continuously contributes new neurons to hippocampal circuits and the programmed death of a subset of immature cells provides a primary mechanism controlling this contribution. Epileptic seizures induce strong structural changes in the hippocampus, including the induction of adult neurogenesis, changes in gene expression and mitochondrial dysfunction, which may all contribute to epileptogenesis. However, a possible interplay between this factors remains largely unexplored. Here, we investigated gene expression changes in the hippocampal dentate gyrus shortly after prolonged seizures induced by kainic acid, focusing on mitochondrial functions. Using comparative proteomics, we identified networks of proteins differentially expressed shortly after seizure induction, including members of the BCL2 family and other mitochondrial proteins. Within these networks, we report for the first time that the atypical BCL2 protein BCL2L13 controls caspase-3 activity and cytochrome C release in neural stem/progenitor cells. Furthermore, we identify BCL2L13 as a novel target of the cooperative action of microRNA-124 and microRNA-137, both upregulated shortly after seizure induction. This cooperative microRNA-mediated fine-tuning of BCL2L13 expression controls casp3 activity, favoring non-apoptotic caspase-3 functions in NSPC exposed to KA and thereby may contribute to the early neurogenic response to epileptic seizures in the dentate gyrus.
Insights
Epileptic seizures alter mitochondrial function and gene expression in the hippocampus. A novel protein, BCL2L13, regulates cell death pathways in neural stem cells following seizures.
Area of Science:
- Neuroscience
- Cell Biology
- Epilepsy Research
Background:
- Adult neurogenesis in the hippocampus is crucial for brain function.
- Epileptic seizures induce significant hippocampal changes, including altered neurogenesis and mitochondrial dysfunction.
- The interplay between these seizure-induced changes and neurogenesis regulation is not well understood.
Purpose of the Study:
- To investigate gene expression and mitochondrial function changes in the hippocampus post-seizure.
- To identify key molecular players regulating neural stem/progenitor cell (NSPC) fate after seizures.
- To explore the role of BCL2 family proteins and microRNAs in the neurogenic response to seizures.
Main Methods:
- Comparative proteomics analysis of hippocampal dentate gyrus tissue after kainic acid-induced seizures.
- Investigation of mitochondrial protein expression and function.
- Analysis of microRNA (miRNA) expression and their targets, specifically focusing on BCL2L13.
Main Results:
- Proteomics identified differential expression of BCL2 family members and mitochondrial proteins post-seizure.
- BCL2L13 was identified as a key regulator of caspase-3 activity and cytochrome C release in NSPCs.
- BCL2L13 is a novel target of miR-124 and miR-137, which are upregulated after seizures, modulating caspase-3 activity.
Conclusions:
- BCL2L13 plays a critical role in controlling cell death pathways in hippocampal NSPCs following epileptic seizures.
- Cooperative regulation of BCL2L13 by miR-124 and miR-137 fine-tunes caspase-3 activity.
- This miRNA-mediated regulation of BCL2L13 promotes non-apoptotic functions of caspase-3, potentially contributing to the early neurogenic response in the dentate gyrus after seizures.
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