Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity
Fig 7
CHIR99021 promotes dorsal subventricular zone (dSVZ)-derived cortical oligodendrocyte (OL) regeneration following chronic hypoxia.
(A) Schematic representation of the experimental workflow. A Cre plasmid was electroporated in the dSVZ of ROSA-YFP mice 1 day after birth (P1) for permanent labeling of dorsal neural stem cells (NSCs). Mice were placed in a hypoxic chamber containing 10% O2 from P3 to P11 then subjected to intranasal CHIR99021 administration from P11 to P13. Animals were sacrificed at P19 for analysis of recombined cell number, migration, and differentiation. (B) Schematic representation of the results quantified in (C-E). (C-D) CHIR99021 treatment following hypoxia leads to a decrease of YFP+ cells in the dSVZ (C), paralleled by a concomitant increase in the cortex (n = 4 for hypoxic and n = 4 for CHIR99021) (D). (E) The average distance of the ten farthest YFP+ cells from the dorsal SVZ is increased following CHIR99021 treatment (n = 4 for hypoxic and n = 3 for CHIR99021). (F-G) CHIR99021 treatment promote de novo oligodendrogenesis (F), YFP+/Olig2+, and neurogenesis (G), YFP+/NeuN+; left confocal micrographs following hypoxia (n = 7 for hypoxic and n = 6 for CHIR99021). Right confocal micrographs show expression of CC1 in YFP+ cells in the most superficial cortical layers, supporting the successful differentiation of the newborn OLs (large arrow) that support myelin (small arrow shows colocalizing YFP+/MBP+ myelinated fibers) in CHIR99021 treated animals. ***p < 0.001; **, p < 0.01; *, p < 0.05; t test used throughout. Scale bars = 20 μm throughout.