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In HeLa cells, transfection with mir-124 can cause a significant change
in the transcriptome profile, making it more similar to that of the brain
( Lim et al ., 2005 ). Changes in transcriptome specificity also arise from the
effect of mir-124 on alternative splicing ( Makeyev et al ., 2007 ). mir-124
targets a repressor of alternative splicing called PTBP1 in the nervous
system; this, in turn, allows for alternative splicing of another splicing
regulator, PTBP2, resulting in correctly spliced and functional PTBP2.
Increased levels of PTBP2 in the nervous system correlate with neural
specific alternative splicing patterns and are necessary for proper neuronal
differentiation.
Other in vitro experiments using ESCs or other cell lines have shown that
mir-124 induces neuronal like differentiation, although in most cases,
additional proneurogenic factors were required to uncover the effect of
mir-124 (reviewed in Maiorano and Mallamaci, 2010 ). More recently, the
neurogenic effect of mir-124 has been explored in vivo . In mouse models,
mir-124 has been shown to promote neurogenesis in the embryonic cere-
bral cortex ( Maiorano and Mallamaci, 2009 ), as well as to control the timing
of progression down the lineage during adult neurogenesis in the stem-cell
niche of the subventricular zone ( Cheng et al ., 2009 ). In the embryonic
cortex, a dramatic upregulation in mir-124 expression in the precursors
undergoing direct neurogenesis as well as gain-of-function experiments
support the role of mir-124 as an inducer of neurogenesis ( Maiorano and
Mallamaci, 2009 ). Although no specific target of mir-124 was shown to be
responsible for this effect, a more recent study also analyzing progenitors in
the developing cortex identified the Ephrin EfnB1 as a relevant target of
mir-124 ( Arvanitis et al ., 2010 ). Interestingly, mir-124 and EfnB1 form a
cross-repressive loop resulting in two states, one with high EfnB1 and low
mir-124 that correlates with maintenance of the progenitor pool, and one
with high mir-124 and low EfnB1 that
seems
to promote neuronal
differentiation.
In the chick spinal cord, the role of mir-124 in neurogenesis has been
somewhat controversial. In a first report, no effects of mir-124 overexpres-
sion or inhibition were observed ( Cao et al ., 2007 ). However, a different
study showed subtle yet noticeable increase in neuronal differentiation at
the expense of proliferation of neural progenitors upon mir-124 overex-
pression ( Visvanathan et al ., 2007 ), again suggesting that mir-124 plays a role
in neurogenesis but may not be strictly sufficient. In the chick spinal cord,
mir-124 is able to repress SCP1 (small C-terminal domain phosphatase 1) an
antineural factor that is recruited by REST to its target genes. However, the
effect of mir-124 in spinal cord neurogenesis is mediated only in part by
repression of SCP1, as a mir-124-insensitive SCP1 transcript could only
partially counteract the neurogenic function of mir-124. Subsequent work
has shown that indeed, mir-124 acts on a number of additional targets to
favor neurogenesis. Moreover, it is possible that mir-124 acts in conjunction
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