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

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 postnatal and adult brain. It contains neural stem cells (NSCs) that give rise to neurons and oligodendrocytes (OLs) in a region-specific manner. Here, we use a bioinformatics approach to identify multiple signaling pathways that regulate the diversity of cell lineages that originate from different subregions of the SVZ. We further use a computational-based drug-discovery strategy to identify a catalogue of small molecules that can be used to manipulate the regionalization of the SVZ. We provide proof that, by administration of small molecules in vivo, it is possible to promote the specific generation of neurons and OLs from NSCs in both the postnatal and adult brain, as well as in regenerative contexts after lesion. This study unravels novel strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.