Dendritic BC1 RNA: Functional Role in Regulation of Translation Initiation

Abstract

In neurons, local protein synthesis in synaptodendritic microdomains has been implicated in the growth and plasticity of synapses. Prerequisites for local translation are the targeted transport of RNAs to distal sites of synthesis in dendrites and translational control mechanisms to limit synthesis to times of demand. Here we identify dendritic BC1 RNA as a specific repressor of translation. Experimental use of internal ribosome entry mechanisms and sucrose density gradient centrifugation showed that BC1-mediated repression targets translation at the level of initiation. Specifically, BC1 RNA inhibited formation of the 48S preinitiation complex, i.e., recruitment of the small ribosomal subunit to the messenger RNA (mRNA). However, 48S complex formation that is independent of the eukaryotic initiation factor 4 (eIF4) family of initiation factors was found to be refractory to inhibition by BC1 RNA, a result that implicates at least one of these factors in the BC1 repression pathway. Biochemical experiments indicated a specific interaction of BC1 RNA with eIF4A, an RNA unwinding factor, and with poly(A)-binding protein. Both proteins were found enriched in synaptodendritic microdomains. Significantly, BC1-mediated repression was shown to be effective not only in cap-dependent translation initiation but also in eIF4-dependent internal initiation. The results suggest a functional role of BC1 RNA as a mediator of translational control in local protein synthesis in nerve cells.

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice

“…Without even considering epistatic consequences [3] of BC1 RNA deletion, the hypothesised role of BC1 RNA in translation modulation is obviously rather generalised and would apply to all cell types that express the RNA [21,[43][44][45]48]. Therefore, effects of the RNA on behavioural phenotype would be determined by the nature of BC1 RNAexpressing cell types, and the nature of the proteins, whose synthesis is subject to BC1 RNA-mediated control in such cells.…”

“…It is a candidate gene responsible for functions that may be underlying novel behavioural patterns in a mammalian order. BC1 RNA has been suggested to operate in the regulation of dendritic protein synthesis, or alternatively as a mediator of dendritic mRNA transport [43][44][45]48]. In an initial analysis, however, the latter notion was shown to be unlikely [41].…”

“…Initially, due to the origin of BC1 RNA by retropositional duplication of a transfer RNA (tRNA Ala ) in conjunction with its unique expression pattern in the rodent nervous system [15,45], a role in regulation of post-synaptic protein synthesis had been suggested [10,45]. The biochemical role of BC1 RNA in translation recently received experimental support [21,48]. Due to the evolutionarily young age of BC1 RNA we anticipated that its elimination would not affect basic memory performance or simple behavioural routines.…”

The RNA binding protein FMRP: new connections and missing links

“…In these mRNPs, the mRNAs would be maintained translationaly silenced through the formation of a complex with FMRP and noncoding RNAs. Consistent with this view, BC1 RNA has been demonstrated to be a specific repressor of translation (Wang et al, 2002). These complexes are likely to be maintained silent throughout their transport until the protein translation resumes when a particular signal is delivered (e.g.…”

“…The mRNAs proposed to be under the control of FMRP via BC1/BC200 are Arc, a-CaMKII, and MAP1B, which had been previously demonstrated to be localized in dendrites or play some important neuronal function. Moreover, BC1 RNA was recently shown to be involved in translational repression at the level of initiation (Wang et al, 2002).…”