Elucidating the cellular and molecular divergence of the human cerebellum

ongoing

Speciation involves the emergence of new behavioural features that rely on the evolution of neural circuits. The human species displays higher cognitive features which have been linked in part to the evolution of the cerebral cortex, but the involvement of the other brain regions, such as the cerebellum, remains largely unexplored. The human cerebellum displays divergent features at the anatomical, functional, and behavioural levels. It is associated with both higher cognitive functions and cognitive disorders. However, the properties of human cerebellar cells & circuits have not been compared with those of other species, including non-human primates. This knowledge gap hinders our understanding of human brain evolution. Here, I aim to identify and functionally study the impact of human genomic novelties on cerebellum development and function, focusing on neuronal and & circuit levels. I will first investigate the role of a novel human molecular pathway in the cerebellum, based on the hominid transmembrane receptor family LRRC37, which I have recently identified. I will identify the cellular distribution, molecular partners, and function of LRRC37 receptors in cerebellar neurons using three approaches: cross-species tissue comparison, gain-of-function in vivo in the mouse cerebellum, and human models based on pluripotent stem cells. In parallel, I will identify new molecular novelties acting in human cerebellar cells, focusing on human gene duplicates and differentially expressed genes, and link them to divergent cerebellar properties. I will define the spatio-temporal expression patterns of these genes, followed by gain/loss-of-function in the mouse cerebellum and in human cerebellar neurons to study their function. Together, hCerebEvol will uncover entirely new aspects of human cerebellar evolution that will improve our understanding of brain development and function, and may lead to the identification of human-specific sensitivity to brain disorders.