The subventricular zone of the mammalian brain is the major source of adult born neurons. These neuroblasts normally migrate long distances to the olfactory bulbs but can be re-routed to locations of injury and promote neuroregeneration. Mechanistic understanding and pharmacological targets regulating neuroblast migration is sparse. Furthermore, lack of migration assays limits development of pharmaceutical interventions targeting neuroblast recruitment. We therefore developed a physiologically relevant 3D neuroblast spheroid migration assay that permits the investigation of large numbers of interventions. To verify the assay, 1,012 kinase inhibitors were screened for their effects on migration. Several induced significant increases or decreases in migration. MuSK and PIK3CB were selected as putative targets and their knockdown validated increased neuroblast migration. Thus, compounds identified through this assay system could be explored for their potential in augmenting neuroblast recruitment to sites of injury for neuroregeneration, or for decreasing malignant invasion.
Journal article
Stem Cell Reports
08/09/2020
15
789 - 802
3D, assay, cancer, drug discovery, imaging, migration, neuroblasts, regenerative medicine, screen, subventricular zone, Animals, Automation, Biological Assay, Cell Movement, Class I Phosphatidylinositol 3-Kinases, Fluorescent Dyes, Gene Knockdown Techniques, Image Processing, Computer-Assisted, Lateral Ventricles, Mice, Neurons, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Receptors, Cholinergic, Reproducibility of Results, Spheroids, Cellular, Time-Lapse Imaging