Defining human-specific rhombic lip developmental mechanisms

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PROJECT SUMMARY While the human cerebellum is traditionally associated with motor functions, recent studies have implicated the cerebellum in higher-order brain functions like speech, language, and even satiety. The cerebellum has dramatically expanded in size across primate evolution so that 80% of human neurons are in the cerebellum. We have identified several human-specific developmental features that are absent in commonly studied animal models. These features include spatiotemporally expanded progenitor zones, including the rhombic lip that produces all cerebellar glutamatergic neurons and an expanded ventricular zone that produces GABAergic neurons. The human RL is long-lived, present throughout the entirety of gestation and exhibits considerable structural and molecular substructure; features not seen in rodents and non-human primates. The unique developmental features of the human cerebellum explains why modeling of human cerebellar developmental disorders has been challenging. However, by studying human cerebellar development, we have now shown that defects in rhombic lip development are implicated in human cerebellar malformations associated with vermian hypoplasia, as well as devastating pediatric brain tumors like Medulloblastoma. Yet, the cellular and molecular mechanisms that drive human-specific expansion of the cerebellar rhombic lip remain unknown. This study aims to better characterize this dorsal cerebellar progenitor zone throughout development using a combination of immunohistochemical and in situ hybridization assays. We will also conduct rigorous spatial and single-cell transcriptome analyses of this progenitor zones to define the molecular pathways driving its development. Lastly, we will study the human rhombic lip in the context of cerebellar malformations to identify aberrant molecular programs contributing to vermian hypoplasia. This study leverages our substantial expertise of cerebellar development in human and other animal models, together with unique samples of normal and pathological human fetal tissue obtained from our extensive network of clinical collaborators.