Two previously undescribed members of the mouse CPEB family of genes and their inducible expression in the principal cell layers of the hippocampus

Cytoplasmic polyadenylation element-binding (CPEB) proteins control polyadenylation-induced translation in early development. Studies in oocytes led to the delineation of Xenopus CPEB, the first member of the family to be identified, and its mouse homologue mCPEB-1. Recently, a second mouse family member, mCPEB-2, has been described in germ cells. Increasing evidence also implicates CPEB proteins as being important in the hippocampus, where these proteins are thought to regulate local protein synthesis and synaptic plasticity. We therefore carried out a systematic screen for CPEB genes in the mouse brain and report two previously undescribed gene family members: mCPEB-3 and -4. We next examined the expression of all four genes in the hippocampus and found that mCPEB-1, -2, and -4 transcripts are expressed in the principal cell layer in the CA3 and CA1 region and in the dentate gyrus of the hippocampus. mCPEB-3 was barely expressed in naïve animals but together with mCPEB-4 was strongly up-regulated after injection of kainate to initiate seizure activity. Whereas mCPEB-1 is regulated by the Aurora kinase, mCPEB-2, -3, and -4 do not contain Aurora kinase phosphorylation sites. However, alternative splice isoforms of mCPEB-2, -3, and -4 encode the so-called B region with phosphorylation sites for cAMP-dependent protein kinase, calcium/calmodulin-dependent protein kinase II, and S6 kinase. Only isoforms that encode the B region were expressed in the principal cell layer. Coexpression of mCPEB-1 and the B region-containing splice isoforms suggests that a variety of different signaling pathways can recruit CPEB activity in hippocampal neurons.

[1]  E. Krebs,et al.  Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. , 1991, The Journal of biological chemistry.

[2]  K. Fukunaga,et al.  A role of Ca2+/calmodulin-dependent protein kinase II in the induction of long-term potentiation in hippocampal CA1 area , 1996, Neuroscience Research.

[3]  Eric R Kandel,et al.  Local protein synthesis and its role in synapse-specific plasticity , 2000, Current Opinion in Neurobiology.

[4]  Alcino J. Silva,et al.  Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[5]  N. Standart,et al.  Dual roles of p82, the clam CPEB homolog, in cytoplasmic polyadenylation and translational masking. , 1999, RNA.

[6]  J. H. Schwartz,et al.  The cytoplasmic polyadenylation element binding protein and polyadenylation of messenger RNA in Aplysia neurons , 2003, Brain Research.

[7]  B. Morris,et al.  In situ hybridization protocols for the Brain , 1994 .

[8]  E. Kandel,et al.  A Transient, Neuron-Wide Form of CREB-Mediated Long-Term Facilitation Can Be Stabilized at Specific Synapses by Local Protein Synthesis , 1999, Cell.

[9]  T. Bliss,et al.  Subfield‐specific immediate early gene expression associated with hippocampal long‐term potentiation in vivo , 2001, The European journal of neuroscience.

[10]  R. Méndez,et al.  Differential mRNA translation and meiotic progression require Cdc2‐mediated CPEB destruction , 2002, The EMBO journal.

[11]  U. Frey,et al.  Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro , 1988, Brain Research.

[12]  R. Méndez,et al.  Translational control by CPEB: a means to the end , 2001, Nature Reviews Molecular Cell Biology.

[13]  A. Gingras,et al.  Regulation of translation initiation by FRAP/mTOR. , 2001, Genes & development.

[14]  M. Kimura,et al.  CPEB2, A Novel Putative Translational Regulator in Mouse Haploid Germ Cells1 , 2003, Biology of reproduction.

[15]  E. Kandel,et al.  Requirement of a critical period of transcription for induction of a late phase of LTP. , 1994, Science.

[16]  P. Schedl,et al.  An autoregulatory feedback loop directs the localized expression of the Drosophila CPEB protein Orb in the developing oocyte. , 2001, Development.

[17]  B. Kemp,et al.  Protein kinase recognition sequence motifs. , 1990, Trends in biochemical sciences.

[18]  Yi-shuian Huang,et al.  N‐methyl‐D‐aspartate receptor signaling results in Aurora kinase‐catalyzed CPEB phosphorylation and αCaMKII mRNA polyadenylation at synapses , 2002, The EMBO journal.

[19]  L. Pinna,et al.  How do protein kinases recognize their substrates? , 1996, Biochimica et biophysica acta.

[20]  M. Mayford,et al.  Disruption of Dendritic Translation of CaMKIIα Impairs Stabilization of Synaptic Plasticity and Memory Consolidation , 2002, Neuron.

[21]  E. Quinlan,et al.  CPEB-Mediated Cytoplasmic Polyadenylation and the Regulation of Experience-Dependent Translation of α-CaMKII mRNA at Synapses , 1998, Neuron.

[22]  E. Kandel,et al.  The 3'-untranslated region of CaMKII alpha is a cis-acting signal for the localization and translation of mRNA in dendrites. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  O. Steward,et al.  Protein synthesis at synaptic sites on dendrites. , 2001, Annual review of neuroscience.

[24]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[25]  J. Richter,et al.  Selective translation of mRNAs at synapses , 2002, Current Opinion in Neurobiology.

[26]  Joel D. Richter,et al.  Phosphorylation of CPE binding factor by Eg2 regulates translation of c-mos mRNA , 2000, Nature.

[27]  A. Gingras,et al.  A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Bear,et al.  A Role for the Cytoplasmic Polyadenylation Element in NMDA Receptor-Regulated mRNA Translation in Neurons , 2001, The Journal of Neuroscience.

[29]  J. Richter,et al.  Germ cell differentiation and synaptonemal complex formation are disrupted in CPEB knockout mice. , 2001, Developmental cell.

[30]  Leszek Kaczmarek,et al.  Kainate-induced genes in the hippocampus: lessons from expression patterns , 2001, Neurochemistry International.