| The cerebellum, one of the primary centers for motor coordination, is organized into a complex set of folia with a stereotypical layered cytoarchitecture. Since folia in mammals likely serve as a broad platform on which the anterior-posterior organization of the sensory-motor circuits of the cerebellum are built, it is important to understand how such complex morphology arises. Establishment of cerebellar cytoarchitecture occurs simultaneously with the process of foliation. To be able to fully understand cerebellum function, it is therefore critical to understand the development of cerebellar cytoarchitecture, as well as its role in the process of foliation. Using a combination of Genetic Inducible Fate Mapping, high-resolution cellular analysis and mutant studies in mouse, I have demonstrated that a key event in initiation of foliation is the acquisition of a distinct cytoarchitecture of Purkinje cells, granule cell precursors and Bergmann glia, in the regions that will become the base of each fissure. I propose to term these regions "anchoring centers". Furthermore, I have demonstrated that changing the timing of anchoring center formation leads to predictable changes in the shape and size of the surrounding folia. To gain insight into the development of cerebellar cytoarchitecture, and determine whether a cell's final position is influenced by its birthdate, and thus its function in the cerebellum, I constructed a temporal fate map of neurons and glia derived from the cerebellar ventricular zone based on their expression of Mash1. I found that Purkinje cells are born from embryonic day 10.5 to 12.5, and migrate to obtain a distinct medial-lateral organization. I also found that Bergmann glia are generated around embryonic day 13.5, whereas astrocytes and oligodendrocytes transiently express Mash1 from embryonic day 13.5 to postnatal day 4. Finally, I demonstrated that cerebellar interneurons differentiate and colonize cellular layers in inside-out fashion. Thus, the cytoarchitecture of the cerebellum arises from a highly regulated differentiation program in the ventricular zone. |
