Synergic Functions of miRNAs Determine Neuronal Fate of Adult Neural Stem Cells.
Adult neurogenesis requires the precise control of neuronal versus astrocyte lineage determination in neural stem cells. While microRNAs (miRNAs) are critically involved in this step during development, their actions in adult hippocampal neural stem cells (aNSCs) has been unclear. As entry point to address that question we chose DICER, an endoribonuclease essential for miRNA biogenesis and other RNAi-related processes. By specific ablation of Dicer in aNSCs in vivo and in vitro, we demonstrate that miRNAs are required for the generation of new neurons, but not astrocytes, in the adult murine hippocampus. Moreover, we identify 11 miRNAs, of which 9 have not been previously characterized in neurogenesis, that determine neurogenic lineage fate choice of aNSCs at the expense of astrogliogenesis. Finally, we propose that the 11 miRNAs sustain adult hippocampal neurogenesis through synergistic modulation of 26 putative targets from different pathways.
Neurobiology of miRNA Lab, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
Meritxell
M
Pons-Espinal
Neurobiology of miRNA Lab, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
Emanuela
E
de Luca
Center for Genomic Science, Istituto Italiano di Tecnologia, IFOM-IEO CAMPUS, Via Adamello 16, 20139 Milan, Italy.
Matteo Jacopo
MJ
Marzi
Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Ruth
R
Beckervordersandforth
D3 PharmaChemistry, Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
Andrea
A
Armirotti
Center for Genomic Science, Istituto Italiano di Tecnologia, IFOM-IEO CAMPUS, Via Adamello 16, 20139 Milan, Italy.
Francesco
F
Nicassio
German Center for Neurodegenerative Diseases (DZNE) Dresden, Arnoldstraße 18/18b, 01307 Dresden, Germany; CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
Klaus
K
Fabel
German Center for Neurodegenerative Diseases (DZNE) Dresden, Arnoldstraße 18/18b, 01307 Dresden, Germany; CRTD - Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
Gerd
G
Kempermann
Neurobiology of miRNA Lab, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. Electronic address: davide.depietri@iit.it.
Davide
D
De Pietri Tonelli
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics
D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
DICER; adult neurogenesis; astrogliogenesis; fate choice; hippocampus; microRNAs; mouse; neural stem cells; synergy