Neuronal BC1 RNA: Microtubule-dependent Dendritic Delivery

Abstract

RNA localization is an important means of post-transcriptional regulation of gene expression in many eukaryotic cell types. In neurons, select RNAs are delivered to postsynaptic dendritic microdomains, a mechanism that is considered a key underpinning in the administration of long-term synaptic plasticity. BC1 RNA is a small untranslated RNA that interacts with translation initiation factors and functions as a translational repressor by targeting assembly of 48S initiation complexes. BC1 RNA is specifically and rapidly transported to dendrites where it is found concentrated in postsynaptic microdomains. The cytoskeletal infrastructure underlying dendritic localization of BC1 RNA has not been investigated. We now report that the dendritic delivery of BC1 RNA is dependent on intact microtubules. In two neuronal cell types, hippocampal neurons and sympathetic neurons in primary culture, disruption of microtubules abolished dendritic localization of BC1 RNA. In contrast, disruption of actin filaments had no significant effect on the somatodendritic distribution of BC1 RNA. It is concluded that the long-range dendritic delivery of BC1 RNA is supported by microtubules. At the same time, a role for actin filaments, while unlikely for long-range BC1 delivery, is not ruled out for short-range local translocation and anchoring at dendritic destination sites.

Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

“…The interaction with BC1 RNA seems to be crucial for its involvement in translation regulation because this small noncoding RNA has the potential to base pair to neuronal target mRNAs, connecting the mRNAs and FMRP (14,40,60,61). BC1 RNA, as FMRP, is efficiently transported along dendrites and axons (38,(62)(63)(64)(65) through a process requiring intact microtubules. In vitro, BC1 has been shown to act as translational repressor of chimeric mRNAs (66,67).…”

Cis-acting determinants of asymmetric, cytoplasmic RNA transport

“…The non-proteincoding, dendritically localized BC1 RNA contains a 62 nucleotide (nt) zipcode at its 59 end (Muslimov et al 1997), which is unlikely to contain multiple, independently functioning subelements due to its short length. This zipcode may directly recruit the machinery responsible for transporting it in a single microtubule-dependent step (Cristofanilli et al 2006), and the RNA may not have cisacting sequences for transport by redundant mechanisms. Another dendritically localized transcript, the MAP2 mRNA, contains a 640 nt element in its 39 UTR that is necessary and sufficient for transport (Blichenberg et al 1999).…”

Asymmetrical N4,N9-Diacyl Spermines: SAR Studies of Nonviral Lipopolyamine Vectors for Efficient siRNA Delivery with Silencing of EGFP Reporter Gene

“…1,2 Following the discovery of gene silencing in petunia flowers 3,4 and then in animal cells, 5,6 siRNA is making significant progress in clinical trials, however, key obstacles still remain to be overcome. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] siRNA is a 21-24 double stranded nucleic acid with a relatively large molecular weight (~13 kDa) and ~40 negative charges (from the 21 bp phosphates). These physicochemical properties ensure siRNA molecules have poor intracellular uptake and so the major challenge lies in the ability to deliver siRNA efficiently to its site of action, the cytoplasm.…”

“…35 Flow Cytometry (FACS). 9 -Disubstituted spermines asymmetrically acylated with aliphatic chains and steroids.…”