In the nervous system, there are a wide variety of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics and this diversity may enable us to elicit higher brain function. However, the molecular mechanisms underlying the developmental brain are largely unknown. The cerebellum is a good model system to study this issue because a variety of types of neurons are produced.
In this study, we focused on Myeloid ecotropic viral integration site 1 (Meis1) that was expressed in the cerebellum during development. We found that Meis1 was expressed in granule cells, Bergmann glia and neuroepithelial cells in the cerebellar primordium. To understand the function of Meis1, we generated two types of Meis1 conditional knockout mice by crossing Meis1-flox mice with Atoh1-Cre line and with En1-Cre line. In the former cKO mice, Meis1 gene was specifically deleted in the granule cell lineage and in the latter cKO, Meis1 gene was deleted in the whole cerebellum.
In Meis1fl/fl; Atoh1-Cre-Tg, the size of the cerebellum was smaller than that of wild type littermates, yet the number of cerebellar lobules was increased. Interestingly, many Atoh1-positive cells were ectopically observed in deeper regions (parenchyma) of the postnatal cerebellum. These cells showed mitotic features and therefore we suspected they contributed to generating extra lobules.
In Meis1fl/fl; En1-Cre mice, the size of the cerebellum was much smaller than that of wild type or Meis1fl/fl; Atoh1-Cre-Tg mice.In contrast to wild type or Meis1fl/fl; Atoh1-Cre-Tg mice, granule cells could not migrate inner cerebellum. Interestingly, position and morphology of Burgmann glia was disorganized. As Bergmann glia is known to regulate migration of granule cells, dysfunction of Brugmann glia may account for migration disorder of granule cells.
These results suggest that Meis1 plays important roles in differentiation of both granule cells and Bergmann glia, thereby controlling coordinated development of the cerebellum.