Spatial codes in dendritic BC1 RNA

Abstract

BC1 RNA is a dendritic untranslated RNA that has been implicated in local translational control mechanisms in neurons. Prerequisite for a functional role of the RNA in synaptodendritic domains is its targeted delivery along the dendritic extent. We report here that the targeting-competent 5′ BC1 domain carries two dendritic targeting codes. One code, specifying somatic export, is located in the medial-basal region of the 5′ BC1 stem-loop structure. It is defined by an export-determinant stem-bulge motif. The second code, specifying long-range dendritic delivery, is located in the apical part of the 5′ stem-loop domain. This element features a GA kink-turn (KT) motif that is indispensable for distal targeting. It specifically interacts with heterogeneous nuclear ribonucleoprotein A2, a trans-acting targeting factor that has previously been implicated in the transport of MBP mRNA in oligodendrocytes and neurons. Our work suggests that a BC1 KT motif encodes distal targeting via the A2 pathway and that architectural RNA elements, such as KT motifs, may function as spatial codes in neural cells.

Multiplexed Dendritic Targeting of α Calcium Calmodulin-dependent Protein Kinase II, Neurogranin, and Activity-regulated Cytoskeleton-associated Protein RNAs by the A2 Pathway

“…PKM RNA also contains an A2RE-like dendritic-tar- geting element (Muslimov et al, 2006) that binds to hnRNP A2, suggesting that it follows the same A2 pathway. Thus, the A2 pathway may be a general pathway for multiplexed dendritic targeting of several different A2RE RNAs in hippocampal neurons.…”

“…FCCS binding isotherms for binding of hnRNP A2 to A2RE sequences from rat MBP, mouse ␣CaMKII, rat NG, rat ARC RNAs, and antisense are shown in Figure 4, High-affinity sequence-specific binding of A2RE sequences to hnRNP A2 may provide the basis for selectivity in distinguishing A2RE from non-A2RE RNAs in the A2 pathway. A putative A2RE-like sequence from BC1 RNA (Muslimov et al, 2006) did not bind with high-affinity to hnRNP A2 (data not shown), suggesting that this sequence does not mediate dendritic targeting of BC1 RNA by the A2 pathway. Because hnRNP A2 binds with high-affinity to synthetic A2RE oligonucleotides, which presumably have little secondary structure, interaction with hnRNP A2 may not require extensive secondary structure.…”

“…Alternatively, complementary base pairing between the A2RE sequence and other sequences in the RNA may constrain certain positions. In this regard, Muslimov proposed that A2RE-like sequences in MBP, PKM , and BC1 RNA are contained within larger "kink-turn" secondary structure motifs (Muslimov et al, 2006). If A2RE sequences in ␣CaMKII, NG, and ARC RNAs are also contained within secondary structure motifs that are necessary for hnRNP A2 binding and dendritic targeting by the A2 pathway, this could constrain certain positions in the A2RE-like sequence.…”

“…MBP RNA contains two partially overlapping A2RE sequences (GCCAAGGAGCC and GCCAGAGAGCC) (Munro et al, 1999), and A2RE sequences have also been identified in the gag and vpr genes of human immunodeficiency virus (HIV) (Mouland et al, 2001). A2RE-like sequences have been noted in dendritically localized neuronal RNAs protein kinase M (PKM ) (Muslimov et al, 2004) and BC1 (Muslimov et al, 2006), but it is not known whether these RNAs are targeted by the A2 pathway. Because polymorphisms at several positions in the A2RE sequence are compatible with hnRNP A2 binding and dendritic targeting (Munro et al, 1999) sequence homology alone is not sufficient to identify functional A2RE sequences.…”

BDNF-induced local protein synthesis and synaptic plasticity

“…The A2RE-dependent targeting of mRNAs is also involved in the dendritic delivery of Arc, CaMKIIa, and Neurogranin mRNAs, which appear to cluster in the same hnRNPA2-containing granules (Gao et al, 2008). Moreover, hnRNPA2 was also shown to be necessary for the delivery of the non-coding BC1 RNA and PKMz mRNA to distal dendritic domains (Muslimov et al, 2006(Muslimov et al, , 2011. (Cajigas et al, 2012;Lein et al, 2007;Poon et al, 2006;Zhong et al, 2006) was compared with the rat genes present in the Agilent Technologies Whole Rat Genome Microarray (https://earray.chem.agilent.com/ earray/catalogGeneLists.do?action¼displaylist#) using GOrilla.…”