Dynamics of the cell division orientation of granule cell precursors during cerebellar development

Abstract

The cerebellar granule cell (GC) system provides a good model for studying neuronal development. In the external granule layer (EGL), granule cell precursors (GCPs) rapidly and continuously divide to produce numerous GCs as well as GCPs. In some brain regions, the orientation of cell division affects daughter cell fate, thus the direction of GCP division is related to whether it produces a GCP or a GC. Therefore, we tried to characterize the orientation of GCP division from embryonic to postnatal stages and to identify an environmental cue that regulates the orientation. By visualizing chromatin in EGL GCPs at M-phase, we found that the directions of cell divisions were not random but dynamically regulated during development. While horizontal and vertical divisions were equivalently observed in embryos, horizontal division was more frequently observed at early postnatal stages. Vertical division became dominant at late cerebellar developmental stages. Administration of a SHH inhibitor to cultured cerebellar slices resulted in randomized orientation of cell division, suggesting that SHH signaling regulates the direction of cell division. These results provide fundamental data towards understanding the development of GCs.