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lation by transiently interacting with eIF4E. Unlike the case with other known eIF4EBPs, however, maskin-mediated translational control is mRNA-specific because of its interaction with CPEB.

Local Translational Control at the Mitotic Apparatus

At a late stage of oocyte maturation, after the activation of M-phase promoting factor (a heterodimer of cdc2 and cyclin B), ˜90% of the CPEB is destroyed (3). That which remains stable is highly localized to the cortex of the animal pole, which in the embryo will give rise to the ectoderm. After fertilization, CPEB remains concentrated in animal pole blastomeres. Within these cells CPEB, as well as maskin, is localized to the mitotic apparatus (15). At metaphase, these proteins are found along the length of the spindles, although there is a greater concentration of them toward the centrosomes. At prophase and prometaphase, the proteins are concentrated on centrosomes. Although the CPEB-activating kinase Eg2 also is found specifically on centrosomes, other proteins involved in polyadenylation-induced translation [poly(A) polymerase, CPSF, eIF4E], which although not particularly concentrated on the mitotic apparatus, are still coincident with it. These results, plus the observation that cyclin B1 mRNA is colocalized with CPEB on spindles, suggest that local polyadenylation-induced translation could take place on or near the mitotic apparatus (15).

CPEB amino acid residues 168–211, which contain a PEST protein-protein interaction domain, mediate the interaction of this protein with microtubules in vitro and with centrosomes in vivo (15). When injected into embryos, a CPEB protein lacking these residues has little effect on the synthesis and oscillation of cyclin B1 protein during the cell cycle. However, this deletion mutant CPEB protein induces the “delocalization” of cyclin B1 mRNA and protein from mitotic spindles. The result of this delocalization is inhibited cell division and a malformation of the mitotic apparatus, which includes tripolar spindles, spindles detached from centrosomes, and multiple centrosomes. These data indicate that not only is regulated cyclin mRNA translation important for cell division in embryos, but that the critical translational event occurs in association with mitotic spindles. This finding implies that an important cell division-promoting activity of cyclin B1 protein must be directed to spindles. It is worth noting that cyclin protein is also present on the spindles of Drosophila embryos (16) and HeLa cells (17), where it also may have an essential function.

Local Translational Control at Synapses

In the central nervous system, a single neuron may receive input signals from thousands of different cells. A dendrite that receives a signal from a given axon establishes a “tag” at the point of reception (i.e., the synapse), which distinguishes this stimulated synapse from the many others that are not stimulated (18). This tag establishes a history or memory of the stimulated synapse. Thus, synapses are considered to be “plastic” because their response to activation is influenced by their stimulation history. Two forms of synaptic plasticity, the long-lasting phase of long-term potentiation and long-term depression, require new protein synthesis but not new mRNA synthesis (refs. 1921; see also ref. 22). These observations, as well as others demonstrating that many of the components of the protein synthesis machinery, including mRNAs, are present in dendrites, suggest that local translational control by synaptic activation could underlie, at least partially, synaptic plasticity (23, 24).

In mammals, CPEB was first thought to be relatively restricted to germ cells (25). However, subsequent studies showed it to also be present in the hippocampus, the portion of the brain that is responsible for long-term memory. Further analysis demonstrated that CPEB resides in the dendritic layer of the hippocampus, at synapses in cultured hippocampal neurons, and in the postsynaptic density of biochemically fractionated synapses (26). The presence of CPEB at synapses suggested a mechanism of translational control that could influence synaptic strength. It therefore became important to identify the synapto-dendritic mRNA(s) whose translation might be regulated by CPEB.

The gene encoding a-CaMKII is necessary for long-term potentiation (27), a-CaMKII mRNA is present in dendrites (28), and a-CaMKII protein levels increase upon synaptic stimulation (29, 30). These observations, plus the further revelation that the 3' untranslated region of a-CaMKII mRNA contains a CPE (26), suggested that this molecule could be a substrate for CPEB activity and undergo polyadenylation-induced translation. Because CPEB is present in the visual cortex as well as in the hippocampus, the effect of synaptic activity on CPEB-mediated translation could be tested by using dark-reared rats. In this paradigm, light exposure elicits massive synaptic activation in the visual cortex of rats raised in the dark. In such animals, light stimulation induced a-CaMKII mRNA polyadenylation and translational activation (26). Thus, CPEB may control local translation of this (and possibly other) mRNAs in the postsynaptic region and, by extension, synaptic plasticity.

Extant Questions

Although there are clear biological consequences of local CPEB-mediated translational control, many particulars remain obscure. For example, why must cyclin mRNA apparently be translated on spindles to effect cell division? If cyclin mRNA polyadenylation-induced translation is under cycle control, as suggested by the data of Groisman et al. (15), then what are the essential upstream signaling events? Is Eg2-mediated CPEB phosphorylation under cell cycle control, or is cytoplasmic polyadenylation, like nuclear polyadenylation, controlled at the level of poly(A) polymerase phosphorylation (31)? In the brain, many questions remain to be explored, such as whether CPEB is activated by Eg2-catalyzed phosphorylation, and most importantly, whether a CPEB knockout mouse would have impaired synaptic plasticity. Finally, the data of Groisman et al. (15) indicate that not only does CPEB regulate translation on spindles, but that it is also involved in localizing mRNA to the mitotic apparatus. Because several CPE-containing mRNAs are localized in dendrites (28), CPEB might influence this process in neurons as well.

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