Multiplexed RNA trafficking in oligodendrocytes and neurons

Abstract

In oligodendrocytes and neurons genetic information is transmitted from the nucleus to dendrites in the form of RNA granules. Here we describe how transport of multiple different RNA molecules in individual granules is analogous to the process of multiplexing in telecommunications. In both cases multiple messages are combined into a composite signal for transmission on a single carrier. Multiplexing provides a mechanism to coordinate local expression of ensembles of genes in myelin in oligodendrocytes and at synapses in neurons.

Figure 1. Oligodendrocytes and neurons form specialized processes and dendrites, respectively

(A). Oligodendrocyte processes terminate in myelin-like membrane sheets. (B). Network of dendrites elaborated by a neuron in culture.

Figure 2. Multiplexing in oligodendrocytes and neurons

Panel A is a diagram of an oligodendrocyte illustrating multiplexed targeting of multiple different A2RE RNAs from the cell body on the left to myelin compartments on the right. Panel B is a diagram of a neuron illustrating multiplexed dendritic targeting of multiple different A2RE RNAs from the perikaryon on the left to dendritic spines on the right. Panel C is a schematic showing the different molecular components and processes involved in multiplexing.

Figure 3. Cis/trans determinants for translational regulation in MBP and αCaMKII RNAs

MBP mRNA and αCaMKII mRNA contain analogous cis-acting translational regulatory elements: hnRNP A2 response element (A2RE), cytoplasmic polyadenylation element (CPE) and hexanucleotide (HEXA) that bind to cognate trans-acting translational regulatory factors: hnRNP A2 (A2), hnRNP E1 (E1), tumor over expressed gene (TOG), CPE binding protein (CPEB), maskin (MSK), eIF4E (4E), cleavage and polyadenylation specificity factor (CPSF). Binding of maskin to eIF4E RNA inactivates translation. Phosphorylation of CPEB facilitates recruitment of CPSF and polyadenylation of the RNA and also causes maskin to dissociate from eIF4E, facilitating recruitment of 40S ribosomal subunit to the RNA. Binding of hnRNP E1 to hnRNP A2 blocks recruitment of 60S ribosomal subunit preventing translation. Dissociation of hnRNP E1 from hnRNP A2 allows recruitment of 60S ribosomal subunit thereby activating translation.