Regulation of synapse density by Pumilio RNA-binding proteins
Lisa K. Randolph,
Michaela M. Pauers,
José C. Martínez,
Leslie J. Sibener,
Michael A. Zrzavy,
Nyle A. Sharif,
Tatiana M. Gonzalez,
Kapil V. Ramachandran,
Daniel Dominguez,
Ulrich Hengst
Affiliations
Lisa K. Randolph
Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
Michaela M. Pauers
Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
José C. Martínez
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Hematology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Leslie J. Sibener
Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
Michael A. Zrzavy
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Nyle A. Sharif
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Tatiana M. Gonzalez
Integrated Program in Cellular, Molecular and Biomedical Studies, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Kapil V. Ramachandran
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Neuroscience, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Daniel Dominguez
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; RNA Discovery Center, University of North Carolina, Chapel Hill, NC 27599, USA
Ulrich Hengst
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Corresponding author
Summary: 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.
