Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms
Weixiang Guo,
Eric D. Polich,
Juan Su,
Yu Gao,
Devin M. Christopher,
Andrea M. Allan,
Min Wang,
Feifei Wang,
Guangfu Wang,
Xinyu Zhao
Affiliations
Weixiang Guo
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Eric D. Polich
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Juan Su
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Yu Gao
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Devin M. Christopher
Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Andrea M. Allan
Department of Neurosciences, University of New Mexico, Albuquerque, NM 87131, USA
Min Wang
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Feifei Wang
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Guangfu Wang
Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA
Xinyu Zhao
Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA
Fragile X mental retardation protein (FMRP) and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2) is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.
