title: Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kasum
authors.identifier: 0000-0003-3984-4473
authors.initials: K
authors.lastname: Azim
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Angonin
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marcy
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pieropan
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rivera
authors.affiliation: Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Donega
authors.affiliation: IMLS, University of Zurich, Zurich, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Cantù
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, United Kingdom.
authors.forename: Gareth
authors.initials: G
authors.lastname: Williams
authors.affiliation: 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.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Berninger
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Butt
authors.affiliation: Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.|Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Raineteau
mesh_terms: D000818:Animals; D019070:Cell Lineage; D003198:Computer Simulation; D030541:Databases, Genetic; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods; D020547:Lateral Ventricles / Q000378:metabolism*; D051379:Mice; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D059467:Transcriptome
chemical_list: D054852:Small Molecule Libraries