title: Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP.
abstract: For proper mammalian brain development and functioning, the translation of many neuronal mRNAs needs to be repressed without neuronal activity stimulations. We have discovered that the expression of a subclass of neuronal proteins essential for neurodevelopment and neuron plasticity is co-regulated at the translational level by TDP-43 and the Fragile X Syndrome protein FMRP. Using molecular, cellular and imaging approaches, we show that these two RNA-binding proteins (RBP) co-repress the translation initiation of Rac1, Map1b and GluR1 mRNAs, and consequently the hippocampal spinogenesis. The co-repression occurs through binding of TDP-43 to mRNA(s) at specific UG/GU sequences and recruitment of the inhibitory CYFIP1-FMRP complex by its glycine-rich domain. This novel regulatory scenario could be utilized to silence a significant portion of around 160 common target mRNAs of the two RBPs. The study establishes a functional/physical partnership between FMRP and TDP-43 that mechanistically links several neurodevelopmental disorders and neurodegenerative diseases.
authors: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.
authors: Pritha
authors: P
authors: Majumder
authors: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.
authors: Jen-Fei
authors: JF
authors: Chu
authors: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.
authors: Biswanath
authors: B
authors: Chatterjee
authors: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.
authors: Krishna B S
authors: KB
authors: Swamy
authors: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan. ckshen@imb.sinica.edu.tw.
authors: Che-Kun James
authors: CJ
authors: Shen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D049452:Green Fluorescent Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D018091:Receptors, AMPA; D020830:rac1 GTP-Binding Protein; C109916:CYFIP1 protein, human; C000598624:TARDBP protein, human; C085284:microtubule-associated protein 1B
keywords: CYFIP1; FISH; FMRP; Immunofluorescence staining; Live cell imaging; Polysome profile; RNA-IP; TDP-43; Translation initiation