3′UTR of mRNA Encoding CPEB Protein Orb2 Plays an Essential Role in Intracellular Transport in Neurons

Abstract

Intracellular trafficking plays a critical role in the functioning of highly polarized cells, such as neurons. Transport of mRNAs, proteins, and other molecules to synaptic terminals maintains contact between neurons and ensures the transmission of nerve impulses. Cytoplasmic polyadenylation element binding (CPEB) proteins play an essential role in long-term memory (LTM) formation by regulating local translation in synapses. Here, we show that the 3′UTR of the Drosophila CPEB gene orb2 is required for targeting the orb2 mRNA and protein to synapses and that this localization is important for LTM formation. When the orb2 3′UTR is deleted, the orb2 mRNAs and proteins fail to localize in synaptic fractions, and pronounced LTM deficits arise. We found that the phenotypic effects of the orb2 3′UTR deletion were rescued by introducing the 3′UTR from the orb, another Drosophila CPEB gene. In contrast, the phenotypic effects of the 3′UTR deletion were not rescued by the 3′UTR from one of the Drosophila α-tubulin genes. Our results show that the orb2 mRNAs must be targeted to the correct locations in neurons and that proper targeting depends upon sequences in the 3′UTR.

Role of Post-Transcriptional Regulation in Learning and Memory in Mammals

“…For example, the already mentioned protein known as GAP-43 is a presynaptic phosphoprotein that probably functions as a coordinating center for a large group of proteins and kinases involved in axonal structure and function, as well as in synapse plasticity control [ 126 , 127 ]. As long as it concerns the CPEB protein, its importance at the level of synapses has also been confirmed by recent experiments in Drosophila that demonstrated that, when the 3′UTR of its mRNA is deleted, the protein (known as Orb2 in this organism) is no longer specifically localized and, as a result, a clear deficit is found in the process of long-term memory acquisition [ 128 , 129 ]. Recently, it has been suggested that the critical role of CPEB proteins in translational control can depend on protein–protein interaction, based on the low-complexity motifs (LCMs), that indeed keep together different proteins in the already mentioned RNA-containing granules [ 130 ].…”

“…Also, in this case, it seems that the sequence of polyglutamine is essential for memory formation [ 197 ]. However, it is now known that the Drosophila counterpart, Orb2, and the ApCPEB isoform can be found in the soluble form or in the β-sheet-rich amyloid form, which has greater binding capacity for mRNAs and, although they have low sequence homology, both of them have N-terminal domains that drive aggregation, following synapse activation [ 128 , 129 , 200 ].…”