Abstract
Cytoplasmic Polyadenylation Element Binding protein (CPEB) is an RNA binding protein involved in dendritic delivery of mRNA and activity-dependent, polyadenylation-induced translation of mRNAs in the dendritic arbor. CPEB affects learning and memory and impacts neuronal morphological and synaptic plasticity. In neurons, CPEB is concentrated in ribonucleoprotein (RNP) granules that distribute throughout the dendritic arbor and localize near synapses, suggesting that the trafficking of RNP granules is important for CPEB function. We tagged full-length CPEB and an inactive mutant CPEB with fluorescent proteins, then imaged rapid dendritic branch dynamics and RNP distribution using two-photon time-lapse microscopy of neurons in the optic tectum of living Xenopus laevis tadpoles. Though the inactive CPEB mutant transports mRNA in the dendritic arbor, its expression interferes with CPEB-dependent translation because it is incapable of activity-triggered mRNA polyadenylation. In dendrites, the distributions of the active and inactive CPEB-containing RNP granules do not differ; the RNP granules are dense and their positions do not correlate with sites of rapid dendritic branch dynamics or the eventual fate of the dendritic branches. Because CPEB's sensitivity to activity-dependent signaling does not alter its dendritic distribution, it indicates that active sites in the dendritic arbor are not targeted for RNP granule localization. Nevertheless, inactive CPEB accumulates in granules in terminal dendritic branches, supporting the hypothesis that upon activation CPEB and its mRNA cargo are released from granules and are then available for dendritic translation.
Highlights
Restricting mRNA distribution and translation to control the production of the proteins is a conserved mechanism associated with cellular polarization or compartmentalization with many examples across biology (Du et al, 2007; Besse and Ephrussi, 2008)
Cytoplasmic Polyadenylation Element Binding protein (CPEB) and delCPEB puncta are excluded from the nucleus, and the proximal dendrites of the neurons contain a high density of puncta, especially in the primary dendrite (Figure 1)
Developing neurons in the optic tectum can increase the size of their dendritic arbor by orders of magnitude over a period of a few days, and when CPEB activity is disrupted by the overexpression of the delCPEB deletion mutant, the normal processes of branch addition and retraction are prevented, resulting in a severely dwarfed dendritic arbor (Bestman and Cline, 2008)
Summary
Restricting mRNA distribution and translation to control the production of the proteins is a conserved mechanism associated with cellular polarization or compartmentalization with many examples across biology (Du et al, 2007; Besse and Ephrussi, 2008). Neurons are examples of the most morphologically complex cells known, in which, temporally- and spatially restricted protein synthesis from mRNA localized to dendrites or axons contributes to the maintenance of this extreme polarization of neural structure and function (Sutton and Schuman, 2006). To accomplish this precise spatial and temporal control of protein synthesis, mRNA is packaged into ribonucleoprotein (RNP) granules, which contain RNA binding proteins, the mRNAs that they target, elements of the translation apparatus, and motor proteins (Hirokawa, 2006; Kiebler and Bassell, 2006). Examples from other systems (e.g., regulation of axis specification in D. melanogaster embryos; St Johnston, 2005; Lecuyer et al, 2007) clearly demonstrate that the control of mRNA localization produces precise, spatially discrete sites of protein synthesis, the spatial range over which local protein synthesis from RNP granule components affects neuronal function is not clear
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