ABSTRACT
CPEB-1 is a sequence-specific RNA binding protein that stimulates the polyadenylation-induced translation of mRNAs containing the cytoplasmic polyadenylation element (CPE). Although CPEB-1 was identified originally in Xenopus oocytes, it has also been found at postsynaptic sites of hippocampal neurons where, in response to N-methyl-D-aspartate receptor activation, it is thought to induce the polyadenylation and translation of alphaCaMKII and perhaps other CPE-containing mRNAs. Because some forms of synaptic modification appear to be influenced by local (synaptic) protein synthesis, we examined long-term potentiation (LTP) in CPEB-1 knockout mice. Although the basal synaptic transmission of Schaffer collateral-CA1 neurons was not affected in the knockout mice, we found that there was a modest deficit in LTP evoked by a single train of 100 Hz stimulation, but a greater deficit in LTP evoked by one train of theta-burst stimulation. In contrast, LTP evoked by either four trains of 100 Hz stimulation or five trains of theta-burst stimulation were not or were only modestly affected, respectively. The deficit in LTP evoked by single stimulation in knockout mice appeared several minutes after tetanic stimulation. Long-term depression (LTD) evoked by 1 Hz stimulation was moderately facilitated; however, a stronger and more enduring form of LTD induced by paired-pulse 1 Hz stimulation was unaffected. These data suggest that CPEB-1 contributes in the translational control of mRNAs that is critical only for some selected forms of LTP and LTD.
Subject(s)
Hippocampus/metabolism , Long-Term Potentiation/physiology , Neuronal Plasticity/physiology , Synapses/metabolism , Transcription Factors/physiology , Xenopus Proteins , mRNA Cleavage and Polyadenylation Factors/physiology , Action Potentials/drug effects , Action Potentials/genetics , Action Potentials/physiology , Animals , Antimetabolites/pharmacology , Electric Stimulation , Hippocampus/cytology , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Long-Term Potentiation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/drug effects , Neuronal Plasticity/genetics , Organ Culture Techniques , RNA/analysis , RNA, Messenger/analysis , Sirolimus/pharmacology , Synapses/drug effects , Synapses/genetics , Synaptic Transmission/drug effects , Synaptic Transmission/genetics , Synaptic Transmission/physiology , Transcription Factors/drug effects , Transcription Factors/genetics , mRNA Cleavage and Polyadenylation Factors/drug effects , mRNA Cleavage and Polyadenylation Factors/geneticsABSTRACT
CPEB is an mRNA-binding protein that stimulates polyadenylation-induced translation of maternal mRNA once it is phosphorylated on Ser 174 or Thr 171 (species-dependent). Disruption of the CPEB gene in mice causes an arrest of oogenesis at embryonic day 16.5 (E16.5), when most oocytes are in pachytene of prophase I. Here, we show that CPEB undergoes Thr 171 phosphorylation at E16.5, but dephosphorylation at the E18.5, when most oocytes are entering diplotene. Although phosphorylation is mediated by the kinase aurora, the dephosphorylation is due to the phosphatase PP1. The temporal control of CPEB phosphorylation suggests a mechanism in which CPE-containing mRNA translation is stimulated at pachytene and metaphase I.
