Neddylation is required for cerebellar development in mice

The cerebellum undergoes a prolonged and highly coordinated developmental program that is essential for motor and cognitive function, yet the post-translational mechanisms governing this process are not fully understood. Here, we identify neddylation, a ubiquitin-like post-translational modification that conjugates NEDD8 to substrate proteins, as a critical regulator of cerebellar development. We show that the indispensable neddylation pathway component NAE1 is broadly expressed in the developing mouse cerebellum, including radial glia, granule cell lineage cells, Purkinje cells, and Bergmann glia. Conditional ablation of NAE1 in the developing cerebellum leads to significant cerebellar hypoplasia, defective foliation, and disrupted cortical lamination. Loss of NAE1 reduces granule cell progenitor proliferation, perturbs granule cell organization and migration, and compromises Bergmann glial identity and architecture. These cellular abnormalities result in marked disorganized cerebellar layers and altered distribution of neuronal and glial populations. Mechanistically, NAE1 deficiency increased nuclear accumulation of β-catenin, indicating impaired regulation of the Wnt/β-catenin pathway. β-catenin knockdown partially rescued the reduction in granule cell progenitor proliferation and the altered inward migration of granule-lineage cells induced by acute Nae1 deletion. Our findings establish neddylation as a crucial molecular determinant of cerebellar morphogenesis and suggest that disrupting this pathway may contribute to cerebellar malformations and neurodevelopmental disorders.