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with mir-9/mir-9* to robustly reduce REST/SCP1-mediated repression of
neural genes (
Conaco
et al
., 2006
;
Packer
et al
., 2008
).
This is not the only target that is shared by these miRNAs. In the mouse
developing neural tube, mir-124 and mir-9* have also been shown to
cooperate in promoting neurogenesis by repressing a progenitor-specific
subunit of a Swi/Snf-like chromatin-remodeling complex termed BAF.
Chromatin remodeling by BAF is important for the different steps
of neural development and its subunit composition changes accordingly.
By targeting a progenitor-specific subunit of BAF, BAF53a, mir-124, and
mir-9* promote this subunit switch and among other effects, reduce the
proliferation of neural progenitor cells (
Yoo
et al
., 2009
).
The overall picture that emerges from these studies is that in vertebrates,
mir-9 and mir-124 are integral to the successful transition between pro-
genitors and differentiated neurons. They seem to orchestrate this transition
through the regulation of multiple targets, all of which either promote
progenitor proliferation or directly inhibit neuronal differentiation, and
most of which are transcriptional regulators.
2.1.3. Neuron-class differentiation
In the previous section, we discussed the role of miRNAs in the first, more
general aspects of neurogenesis of NSCs that become progressively com-
mitted to giving rise to neurons. However, miRNAs are also involved in
the subsequent steps of defining what type of neurons those committed
precursors will become and in controlling the progression of the differenti-
ation program.
It is widely accepted that distinct cell types are the products of combina-
torial “codes” of gene regulatory factors; these include, but are not limited
to, transcription factors and miRNAs. This aspect of neural development
has been widely studied in the nematode
C. elegans
, where specification of
pan-neuronal features can be genetically separated from neuron-class speci-
fication and where several genes affecting the latter have been identified
(
Hobert, 2011
). In
C. elegans,
mir-124 does not seem to be involved in
neurogenesis as broadly as in other systems, but rather it is expressed in a
subset of sensory neurons and it may play a role in shaping their cell-specific
transcriptome (
Clark
et al
., 2010
). One of the best-studied miRNAs
involved in neuron-class specification, a miRNA called
lsy-6,
also comes
from
C. elegans
.
lsy-6
is responsible for the subclass diversification of the ASE
neurons, a pair of sensory neurons on either side of the head of the worm
(
Johnston and Hobert, 2003
). Despite being bilaterally symmetric with
respect to a number of criteria (position in the head, connectivity, mor-
phology of its projections, and shared gene expression), each ASE neuron
senses different environmental cues and responds to them in different ways.
This is largely due to the presence of
lsy-6
only in the left ASE neuron
(ASEL), where it represses the Nkx6-type transcription factor
cog-1
.
lsy-6
,
