title: MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells.
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.
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.
authors.forename: Marijn
authors.initials: M
authors.lastname: Schouten
authors.affiliation: Oncoproteomics Laboratory, Cancer Center, Free University Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
authors.forename: Silvina A
authors.initials: SA
authors.lastname: Fratantoni
authors.affiliation: 1] Division of Pharmacology, LACDR, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands [2] Foundation of Epilepsy Institutes of The Netherlands (SEIN), Achterweg 5, 2103 SW, Heemstede, The Netherlands.
authors.forename: Chantal J
authors.initials: CJ
authors.lastname: Hubens
authors.affiliation: Oncoproteomics Laboratory, Cancer Center, Free University Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
authors.forename: Sander R
authors.initials: SR
authors.lastname: Piersma
authors.affiliation: Oncoproteomics Laboratory, Cancer Center, Free University Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
authors.forename: Thang V
authors.initials: TV
authors.lastname: Pham
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bielefeld
authors.affiliation: 1] Division of Pharmacology, LACDR, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands [2] Foundation of Epilepsy Institutes of The Netherlands (SEIN), Achterweg 5, 2103 SW, Heemstede, The Netherlands.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.affiliation: Oncoproteomics Laboratory, Cancer Center, Free University Amsterdam, De Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Jimenez
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH, Amsterdam, The Netherlands.
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Fitzsimons
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism* / Q000473:pathology; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018690:Excitatory Amino Acid Agonists; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000607844:BCL2L13 protein, mouse; D018690:Excitatory Amino Acid Agonists; C551799:MIRN137 microRNA, mouse; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; D007608:Kainic Acid