PROJECT SUMMARY The human cerebellum despite its small size relative to the cerebral cortex, contains nearly 80% of all neurons in the brain. While it is classically associated with motor function, recent studies indicate a role for the human cerebellum in higher cognitive functions such as speech, language and even satiety. Cerebellar disease, including malformations and tumors, are common. Yet, our understanding of the cellular and molecular basis of cerebellar disease is poor. One reason for this could be our animal model-centric view of normal and abnormal cerebellar development. We have identified several unique cerebellar developmental features in human that are absent in commonly studied animal models, including rodents and non-human primates like the macaque. These features include spatiotemporally expanded progenitor zones, like the rhombic lip that produces cerebellar glutamatergic neurons and an expanded ventricular zone that produces GABAergic neurons. The rhombic lip in humans is also long-lived and undergoes a series of morphological and cellular changes that are yet to be identified in other animal species. The presence of human-specific features of normal human cerebellar development partly explains why modeling cerebellar disease in animals has been a challenge. This study aims to characterize the cellular features of these expanded progenitor zones in human using a battery of in vitro assays, including live imaging microscopic protocols that measure the proliferative and migratory characteristics of cells residing in these stem cell zones. We will also conduct rigorous single-cell transcriptomic and epigenomic analyses of this progenitor zones to define the molecular pathways driving its development. This study leverages our extensive expertise of cerebellar development in human and other animal models, together with our unique access to fresh normal human fetal tissue obtained at the University college London through the Human Developmental Biology Resource.