Regulation of synapse density by Pumilio RNA-binding proteins

The formation, stabilization, and elimination of synapses are tightly regulated during neural development and into adulthood. Pumilio RNA-binding proteins regulate the translation and localization of many synaptic mRNAs and are developmentally downregulated in the brain. We found that simultaneous downregulation of Pumilio 1 and 2 increases both excitatory and inhibitory synapse density in primary hippocampal neurons and promotes synapse maturation. Loss of Pum1 and Pum2 in the mouse brain was associated with an increase in mRNAs involved in mitochondrial function and synaptic translation. These findings reveal a role for developmental Pumilio downregulation as a permissive step in the maturation of synapses and suggest that modulation of Pumilio levels is a cell-intrinsic mechanism by which neurons tune their capacity for synapse stabilization. [Display omitted] •Pum1 and Pum2 are developmentally downregulated in the brain•Loss of Pum1/2 increases excitatory and inhibitory synapse density and synapse maturation•Loss of Pum1/2 upregulates mRNAs involved in mitochondrial function and synaptic translation Pumilio RNA-binding proteins are developmentally downregulated in the brain. Randolph et al. report that the simultaneous downregulation of Pumilio 1 and 2 promotes synapse maturation and increases the density of excitatory and inhibitory synapses. Thus, the regulation of Pumilio protein levels represents a cell-intrinsic mechanism for the modulation of synapse maturation.