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synaptic mRNAs from the repressed state and into the polysome fraction. In
both systems, CaMKII protein synthesis was increased, but interestingly, so
were Limk1 and Lypla1/APT1 in the rat neurons. These two mRNAs had
previously been shown to be targets of mir-134 (
Schratt
et al
., 2006
) and mir-
138 (
Siegel
et al
., 2009
), respectively, and their repression had been shown to
be relieved at the synapse by neuronal activity.
Overall, miRNA-mediated translational repression seems to be deeply
integrated in the dynamic responses that neurons elicit during activity and to
maintain homeostasis. Their subcellular localization, the rapid kinetics, and
reversibility of their function and their target diversity make them very
suitable to fulfill this role.
3.3. A role for miRNAs in generating neuronal diversity
The cellular diversity in the nervous system is unparalleled by that of any
other organ system. Even an organism with a simple nervous system, such as
C. elegans
, has at least 118 different classes of neurons. In general, the proper-
ties of each cell class are a consequence of the genes each class expresses, and
this is, in turn, defined by the gene regulatory factors present in each cell type.
Transcription factors (TFs) and miRNAs are the two most abundant and
diverse classes of gene expression regulators, and it has been proposed that
combinatorial “codes” of TFs and miRNAs can define all different cell types
(
Hobert, 2004
).
The magnitude of the contribution of miRNAs to generating this
diversity is beginning to be grasped. While a number of examples have
been provided so far, many more are likely to be uncovered. Given their
numbers, high evolvability, their diverse spatial and temporal expression
patterns (
Kapsimali
et al
., 2007
), and their ability to modify preexisting
genetic networks to produce stable, heritable phenotypes, miRNAs are
very good candidates to introduce an additional level of complexity.
We have already discussed the role of
lsy-6
in diversifying two sensory
neurons in
C. elegans
that would otherwise be practically identical. In this
case, it seems likely that the incorporation of a single regulatory factor (
lsy-
6)
into preexisting regulatory networks during evolution could be responsible
for this diversification.
lsy-6
is a nematode-specific miRNA; however, it is
not present in all nematodes. While species such as
Caenorhabditis briggsae
,
Caenorhabditis remanei
, and
Caenorhabditis brenneri
have homologs of
lsy-6
and its target
cog-1, Pristionchus pacificus,
a more distant relative, does not
seem to have a
lsy-6
homolog, and interestingly, while the
cog-1
ORF is
conserved with that of
C. elegans,
their 3
0
UTRs are not. Further analysis of
the properties of the ASE sensory neurons in
Pristionchus
will likely provide
new insight into the incorporation of miRNAs into gene regulatory net-
works during evolution.
