RIM3γ and RIM4γ Are Key Regulators of Neuronal Arborization

The large isoforms of the Rab3 interacting molecule (RIM) family, RIM1 alpha/beta and RIM2 alpha/beta, have been shown to be centrally involved in mediating presynaptic active zone function. The RIM protein family contains two additional small isoforms, RIM3 gamma and RIM4 gamma, which are composed only of the RIM-specific C-terminal C2B domain and varying N-terminal sequences and whose function remains to be elucidated. Here, we report that both, RIM3 gamma and RIM4 gamma, play an essential role for the development of neuronal arborization and of dendritic spines independent of synaptic function. gamma-RIM knock-down in rat primary neuronal cultures and in vivo resulted in a drastic reduction in the complexity of neuronal arborization, affecting both axonal and dendritic outgrowth, independent of the time point of gamma-RIM downregulation during dendrite development. Rescue experiments revealed that the phenotype is caused by a function common to both gamma-RIMs. These findings indicate that gamma-RIMs are involved in cell biological functions distinct from the regulation of synaptic vesicle exocytosis and play a role in the molecular mechanisms controlling the establishment of dendritic complexity and axonal outgrowth.