Author:

Keywords:

Amino Acid Sequence, Animals, Brain, Cells, Cultured, Eukaryotic Initiation Factor-4E, Fragile X Mental Retardation Protein, Mice, Mice, Inbred C57BL, Mice, Knockout, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Protein Biosynthesis, Sequence Alignment, Synapses, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, MENTAL-RETARDATION PROTEIN, INITIATION-FACTOR 4E, MESSENGER-RNA, DROSOPHILA CUP, BC1 RNA, BINDING, FMRP, LOCALIZATION, STABILITY, PATHWAY, Adaptor Proteins, Signal Transducing, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

Strong evidence indicates that regulated mRNA translation in neuronal dendrites underlies synaptic plasticity and brain development. The fragile X mental retardation protein (FMRP) is involved in this process; here, we show that it acts by inhibiting translation initiation. A binding partner of FMRP, CYFIP1/Sra1, directly binds the translation initiation factor eIF4E through a domain that is structurally related to those present in 4E-BP translational inhibitors. Brain cytoplasmic RNA 1 (BC1), another FMRP binding partner, increases the affinity of FMRP for the CYFIP1-eIF4E complex in the brain. Levels of proteins encoded by known FMRP target mRNAs are increased upon reduction of CYFIP1 in neurons. Translational repression is regulated in an activity-dependent manner because BDNF or DHPG stimulation of neurons causes CYFIP1 to dissociate from eIF4E at synapses, thereby resulting in protein synthesis. Thus, the translational repression activity of FMRP in the brain is mediated, at least in part, by CYFIP1.