PP2Acα regulates cerebellar development via phosphorylation-dependent neuronal programs.

Cerebellar development requires precise control of phosphorylation, yet the contribution of protein phosphatases remains poorly understood. Here, we investigated the function of protein phosphatase 2A catalytic subunit alpha (PP2Acα) in cerebellar granule neurons. Conditional deletion of Ppp2ca using Atoh1-Cre mice resulted in impaired motor coordination and cognitive performance, reflecting disrupted cerebellar development. Histological analyses revealed abnormal granule neuron proliferation, migration, and defective Purkinje cell organization during early postnatal stages. Phosphoproteomic and proteomic profiling of primary granule neurons identified the PP2Acα-dependent regulation of cell cycle, cytoskeletal remodeling, RNA splicing, metabolism, and translation. Complementary profiling of whole cerebellar tissues uncovered broader system-level alterations affecting neuronal morphogenesis, mRNA processing, synaptic signaling, and behavior. Collectively, these findings establish PP2Acα as a critical regulator of cerebellar development through coordinated control of phosphorylation and protein homeostasis across cellular and system levels, providing mechanistic insights into phosphatase-related neurodevelopmental disorders.