Translational control at the synapse: role of RNA regulators

Abstract

Translational control of gene expression is instrumental in the regulation of eukaryotic cellular form and function. Neurons in particular rely on this form of control because their numerous synaptic connections need to be independently modulated in an input-specific manner. Brain cytoplasmic (BC) RNAs implement translational control at neuronal synapses. BC RNAs regulate protein synthesis by interacting with eIF4 translation initiation factors. Recent evidence suggests that such regulation is required to control synaptic strength, and that dysregulation of local protein synthesis precipitates neuronal hyperexcitability and a propensity for epileptogenic responses. A similar phenotype results from lack of fragile X mental retardation protein (FMRP), indicating that BC RNAs and FMRP use overlapping and convergent modes of action in neuronal translational regulation.

Figure I

The retroposition mechanism. The sequence is initiated with a nicking of the first (bottom) DNA strand by an endonuclease (step 1). The new 3′ end serves as a primer for reverse transcription of a template RNA (red, step 2) [84]. Second strand cleavage (step 3) occurs during or after reverse transcription. After integration (step 4), the hybrid RNA is degraded, and second strand synthesis ensues (step 5). Newly synthesized DNA strands are in green. Target site duplications (TSDs) are hallmarks of retroposons. They occur because target site cleavage produces staggered ends, and the resulting small gaps are filled in on both sides of the insertion, giving rise to short flanking duplications. Adapted from Kazazian et al. [84], with permission.

Figure I

Noncanonical C-loop motifs. BC RNA C-loop motifs are aligned with a previously described eukaryotic C-loop motif [58]. Canonical and non-canonical nucleotide interactions are indicated. Base pairings are typified using the Leontis and Westhof scheme of symbolic representations [58, 90] as follows: solid symbols, cis pairing; open symbols, trans pairing; lines, cis-WC/WC (green and yellow boxes); solid circle-arrow, cis-WC/SE (blue box); open circle-square, trans-WC/H (purple box). Adapted from Eom et al. [44], with permission. Copyright © American Society for Microbiology.

Figure 1

Ratios of non-protein-coding DNA and megabases of protein-coding regions per haploid genome across species. (a) Ratios of bases in non-protein-coding regions vs. total genomic DNA per sequenced genome. Prokaryotes are in black, unicellular eukaryotes in gray, organisms known to be both uni- and multicellular, depending on lifecycle, in light blue, basal multicellular organisms in blue, plants in green, nematodes in purple, arthropods in orange, chordates in yellow, vertebrates in red. (b) Amount (in megabases) of protein-coding regions per genome for species ranked by fraction of non-protein-coding DNA in (a). Adapted from Taft et al. [33], with permission.

Figure 2. Translational control by BC RNAs and FMRP

Activation of group I mGluRs (metabotropic glutamate receptors) couples to the translational machinery via the MEK-ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) pathway. This translational stimulation is counteracted by two translational repression systems acting in series. BC RNAs (here represented by BC1 RNA) repress assembly of 48S initiation complexes [42, 44] and thus negatively regulate translation that is activated by signaling via the group I mGluR – MEK-ERK pathway [53]. Analogously, FMRP represses translation that is stimulated via this pathway [12, 50]. The asterisks associated with the two red inhibition bars indicate that published evidence has implicated FMRP in the repression of initiation or postinitiation steps, or both. Earlier evidence [14] suggested a role of FMRP in inhibiting formation of 80S ribosomes, but more recent data [23] support a role in stalling elongating ribosomes. The combined actions of translational stimulation and repression are assumed to ensure an appropriate excitability balance at the synapse. Dark green arrows indicate activation, red T-shaped bars indicate inhibition, and light green arrows indicate steps in a pathway.

Figure 3. RNA transport in dendrites

The hnRNP (heterogeneous nuclear ribonucleoprotein) A2 and ZBP1 (zipcode binding protein 1) pathways represent two of the major RNA targeting mechanisms in neurons. hnRNP A2 (blue spheres) interacts with GA-type noncanonical motifs, as exemplified by those in the 5′ domain of BC1 and BC200 RNAs, and in the 3′ UTR of PKMζ mRNA [62]. At the synapse, BC RNAs repress translation (red T-shaped bar) by preventing 48S complex formation [42, 44], thus providing a counterbalance to translational stimulation through group I mGluR activation (dark green arrow; center, right) [53]. hnRNP A2 also interacts with expanded CGG repeat stem-loop structures in the 5′ UTR of premutation FMR1 mRNA (FMR1 mRNA*) [69, 73]. Premutation FMR1 mRNA can compete with GA motif RNAs for access to hnRNP A2, which could lead to impairments in their dendritic delivery [62]. ZBP1 (orange spheres) interacts with the β-actin mRNA zipcode, promoting dendritic delivery of the mRNA while at the same time inhibiting its translation [3]. It is possible that at the synapse, phosphorylation of ZBP1 by Src kinase (bottom, right) causes it to release β-actin mRNA, permitting translation [3]. Black arrows indicate movement and association, dark green arrow indicates stimulation, red T-shaped bars indicate inhibition.