6533b7defe1ef96bd1275f27
RESEARCH PRODUCT
Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity
Kasum AzimDiane AngoninGuillaume MarcyFrancesca PieropanAndrea RiveraVanessa DonegaClaudio CantùGareth WilliamsBenedikt BerningerArthur M ButtOlivier Raineteausubject
animal diseasesGene Identification and AnalysisGenetic NetworksAPC-PAIDMiceNeural Stem CellsCell SignalingLateral VentriclesDatabases GeneticGene Regulatory NetworksBiology (General)WNT Signaling CascadeNotch SignalingOrganic CompoundsBB/M029379/1GenomicsSignaling CascadesOligodendrogliaChemistryBBSRCPhysical Sciences[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Network AnalysisNeurovetenskaperSignal TransductionResearch ArticleBiotechnologyComputer and Information SciencesSignal InhibitionQH301-705.5NeurogenesisResearch and Analysis MethodsSmall Molecule LibrariesGenetics/dk/atira/pure/core/subjects/biomedicalsciencesAnimalsAdultsCell LineageComputer Simulation[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Molecular Biology TechniquesMolecular BiologyOrganic ChemistryGene MappingChemical CompoundsNeurosciencesBiology and Life SciencesRCUKBiomedical SciencesCell BiologyNerve RegenerationSignaling NetworksGene Expression Regulationnervous systemSmall MoleculesAge GroupsPeople and PlacesPopulation GroupingsTranscriptomedescription
Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.
year | journal | country | edition | language |
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2017-03-28 |