Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex.
Translational control of mRNAs in dendrites is essential for certain forms of synaptic plasticity and learning and memory. CPEB is an RNA-binding protein that regulates local translation in dendrites. Here, we identify poly(A) polymerase Gld2, deadenylase PARN, and translation inhibitory factor neuroguidin (Ngd) as components of a dendritic CPEB-associated polyadenylation apparatus. Synaptic stimulation induces phosphorylation of CPEB, PARN expulsion from the ribonucleoprotein complex, and polyadenylation in dendrites. A screen for mRNAs whose polyadenylation is altered by Gld2 depletion identified >100 transcripts including one encoding NR2A, an NMDA receptor subunit. shRNA depletion studies demonstrate that Gld2 promotes and Ngd inhibits dendritic NR2A expression. Finally, shRNA-mediated depletion of Gld2 in vivo attenuates protein synthesis-dependent long-term potentiation (LTP) at hippocampal dentate gyrus synapses; conversely, Ngd depletion enhances LTP. These results identify a pivotal role for polyadenylation and the opposing effects of Gld2 and Ngd in hippocampal synaptic plasticity.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Tsuyoshi
T
Udagawa
Sharon A
SA
Swanger
Koichi
K
Takeuchi
Jong Heon
JH
Kim
Vijayalaxmi
V
Nalavadi
Jihae
J
Shin
Lori J
LJ
Lorenz
R Suzanne
RS
Zukin
Gary J
GJ
Bassell
Joel D
JD
Richter
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D009687:Nuclear Proteins / Q000378:metabolism; D026723:Polyadenylation; D011062:Polynucleotide Adenylyltransferase / Q000378:metabolism; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D009435:Synaptic Transmission; D014157:Transcription Factors / Q000378:metabolism; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism
D009687:Nuclear Proteins; D011062:Polynucleotide Adenylyltransferase; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D039221:mRNA Cleavage and Polyadenylation Factors; C490386:CPEB1 protein, human; C539243:CPEB1 protein, rat; C532399:NGDN protein, human; C101043:SYMPK protein, human; C511175:neuroguidin protein, mouse; C575491:Gld2 protein, mouse; C550174:TENT2 protein, human; C575492:Tent2 protein, rat; C490387:Cpeb1 protein, mouse