Biology Reference
In-Depth Information
miRNAs evolve in a highly dynamic manner with a high birth rate and
presumably also a high rate of incorporation into preexisting gene regu-
latory networks (
Grimson
et al
., 2008
;
Heimberg
et al
., 2008
;
Hobert, 2008
;
Liu
et al
., 2008
;
Lu
et al
., 2008
). The rapid evolvability of miRNAs could
result in the acquisition of diverse targets in different organisms or different
tissues. Interestingly, in those cases where the miRNAs are 100% conserved
and still have distinct targets, some other kind of constraint, either structural
or that imposed by one shared target, must also be in place.
In addition to evolutionary implications, the fact that cellular context
can have such an impact on miRNA function has a very practical conse-
quence: it is definitely an important point to keep in mind when analyzing
potential targets of a miRNA, especially since so many approaches to
validate miRNA targets rely on artificial expression of both miRNA and
target in heterologous systems.
3. Neuronal-Specific Aspects of miRNA Function
3.1. Subcellular localization and spatial regulation
As most posttranscriptional regulators, miRNAs carry out their function in
the cytosol. In neurons, the cytosol is divided in distinct subcellular
domains, the soma, the dendrites, and the axon, and miRNAs have been
detected in all these compartments. Translation regulation of synaptic-
specific mRNAs in the neurites has been shown to provide a fast response,
at the site where it is required, to allow for synaptic plasticity, and miRNAs
are able to participate in these localized regulatory responses. Importantly,
RISC is also present at synaptic terminals, and some of its components are
regulated by neuronal activity, something we will discuss in
Section 3.2
.
While a few miRNAs have been observed to be present or even
enriched in neuronal processes by
in situ
hybridization, four studies under-
took an unbiased approach to identify dendrite- and axon-enriched miR-
NAs. Using different methods, all four managed to isolate miRNAs from
either the soma or the projections and identified a number of miRNAs that
are enriched in the different compartments.
First, Kosik and colleagues isolated miRNAs from the soma or the
dendrites from hippocampal neurons in culture and identified mir-26 and
mir-292-5p as being highly enriched in dendrites (
Kye
et al
., 2007
). Smal-
heiser and colleagues fractionated adult mouse brains and isolated miRNAs
from different synaptic fractions (synaptoneurosomes, enriched in dendritic
spines and synaptosomes, enriched in synaptic membranes); this led to the
identification of subsets of miRNAs enriched in these synaptic fractions as
compared to whole brain homogenates (
Lugli
et al
., 2008
). Further analysis
of these miRNAs will reveal whether they have specific functions at the
