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PLoS Biol. 2017 Mar 28;15(3):e2000698. doi: 10.1371/journal.pbio.2000698. eCollection 2017 Mar.

Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.

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Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany.
Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
IMLS, University of Zurich, Zurich, Switzerland.
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, United Kingdom.


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.

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