| Abstract: | ![]()
In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial “whole-mount” dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system.The nervous system is formed by migration of neuronal precursors and immature neurons to specific locations during development. The classic radial unit hypothesis of mammalian brain development postulates that in the developing neocortex, glutamatergic, excitatory, principal neurons migrate radially to form discrete information-processing columns of ontogenetic origin (1), whereas GABAergic, inhibitory, modulatory interneurons migrate tangentially across columns (2). Neurogenesis persists in the adult mammalian brain in two primary regions and is thought to follow the classic migration model (3, 4). In the subventricular zone (SVZ) of the lateral ventricles, new neurons generated from neural precursors migrate tangentially to the olfactory bulb to become GABAergic interneurons (5, 6). In contrast, in the subgranular zone (SGZ) of the dentate gyrus, new neurons generated from radial glia-like neural stem cells (RGLs) migrate radially into the granule cell layer to become principal glutamatergic granule cells (7). Due to technical challenges, migratory patterns have only been examined at the cell-population level, and thus we still lack detailed information about the spatial relationship between individual precursors and their progeny in vivo. Both adult neurogenic niches are highly vascularized, and this property is hypothesized to play a critical role in adult neurogenesis (3). In both adult SVZ (8–10) and SGZ (11), proliferating progenitor cells are in close association with the vasculature, yet the functional role of the vasculature in the niche remains to be fully explored.Contrary to the classic model, our recent clonal lineage tracing of individual quiescent RGLs showed tangential distribution of glutamatergic granule neurons with respect to their parental RGL in the adult dentate gyrus (12). We therefore systematically investigated the migration pattern and trajectory of these newborn cells. Using a clonal lineage-tracing approach that preferentially targets active RGLs in the adult mouse dentate gyrus, thereby birthdating their newborn progeny in vivo, we found significant tangential distribution of newborn neuroblasts from their parental RGL. Furthermore, neuroblasts directly contact the vascular network, suggesting an important function of blood vessels as a substrate for migration. Together, our results reveal a previously unidentified mode of glutamatergic neuronal migration under physiological conditions in the adult mammalian brain. |
