Investigating Cerebellar Development in Ferrets: Implications for Modelling Human Cerebellar Development and Disease - PROJECT SUMMARY While the human cerebellum is classically known for its involvement in motor functions, recent research has implicated it in higher-order brain functions such as speech, language, and satiety. Across primate evolution, the cerebellum has undergone significant expansion, housing 80% of human neurons. Yet, understanding its development presents challenges due to unique human-specific features absent in commonly studied animal models. Ferrets have emerged as a valuable model for studying various aspects of human brain development due to several key similarities between their brain structure and development with that of humans, including the presence of a gyrencephalic cerebral cortex. We recently identified several distinctive developmental traits in the ferret cerebellum which partially mirror those found in humans. These include the presence of an expanded dorsal progenitor zone called the rhombic lip (RL) which produces all cerebellar Glutamatergic neurons. Compared to rodents like mice and rats, we also observe an expansion in cycling Tbr2+ cells which we recently implicated in the pathogenesis of Medulloblastoma Groups 3 and 4. Notably, our preliminary data also indicates that the ferret RL shares characteristics such as longevity throughout gestation and molecular complexity similar to the human RL, setting it apart from rodents and non-human primates. Despite these parallels, we know very little about cerebellar development in ferrets and the mechanisms driving the ferret- specific expansion of the cerebellar progenitor zones remain elusive necessitating a more comprehensive analysis. This study aims to elucidate this process by characterizing all primary and secondary cerebellar progenitor zone in ferrets throughout development. Utilizing immunohistochemical and in situ hybridization assays, alongside single-cell/nucleus multiomic analyses, we seek to unravel the molecular pathways governing cerebellar development in ferrets. Furthermore, by studying the ferret cerebellum in the context of human and mouse development, we aim to identify unique as well as shared molecular programs. Leveraging our expertise in cerebellar development across multiple species, including ferrets, and our access to unique samples of normal ferret tissue, obtained through collaborative efforts, this study promises to shed light on the intricacies of ferret cerebellar development and its utility as a potential model to study human cerebellar disease.
