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directly activated by a key erythroid transcription factor, Gata-1 ( Dore et al .,
2008 ). Loss-of-function studies in both Zebrafish and mouse revealed that
this conserved miR locus is required for erythroblast maturation ( Dore et al .,
2008; Rasmussen et al ., 2010 ). Interestingly, the mRNA of 14-3-3
, a key
regulator of cytokine signaling, was identified as a direct target of miR-451.
More importantly, knocking down 14-3-3
z
in miR-451 null HSCs rescued
these defects during erythroid differentiation in vitro, providing another
example where a single target may be primarily responsible for mediating
the effects of a miR in a defined cellular context ( Patrick et al ., 2010; Yu
et al ., 2010 ).
z
11. miR Function in Neural Stem Cells
In the adult brain, Dicer ablation results in massive hypotrophy of the
cortex due to neuronal apoptosis, accompanied by a dramatic impairment of
neuronal differentiation ( De Pietri Tonelli et al ., 2008 ). Remarkably, the
neuroepithelial cells and the neurogenic progenitors derived from them
were not grossly affected by depletion of Dicer, suggesting that like the
epidermis, the progenitors are less dependent on miRNAs than their
differentiated progeny.
miR-9 is interesting in that it is expressed specifically in the subven-
tricular zone (SVZ) of the brain known to harbor the neural stem cells
(NSCs). However, miR-9 appears to negatively regulate NSC prolifera-
tion and accelerate neural differentiation ( Zhao et al ., 2009 ). Intriguingly,
TLX, requisite for NSC self-renewal, is a target for miR-9, but, in turn, it
also antagonizes miR-9's expression by directly reducing the transcription
of pri-miR-9 ( Zhao et al ., 2009 ). Thus, TLX and miR-9 form a negative
feedback regulatory network to balance both proliferation and differentia-
tion of NSCs. In this regard, miR-9's effects on NSCs appear to be
distinct from the effects of either miR-125b or miR-203 on skin SCs.
In contrast, miR-124, one of the most specific and abundant miRs in
the brain, more closely mirrors the behavior of miR-203 in skin. Like
miR-203, miR-124 is expressed at low levels in the SVZ stem cell
compartment but is sharply upregulated in mature granule and periglo-
merular neurons ( Cheng et al ., 2009 ). Similarly, gain-of-function of
miR-124 induces cell cycle exit, while inhibition of miR-124 by antag-
omir in vivo results in an increase in the population of precursor cells in
the SVZ. Moreover, Sox9, a key transcription factor whose downregula-
tion is required for neural differentiation, has been identified as a direct
target of miR-124 ( Cheng et al ., 2009 ). In this regard, the effect of
miR-124 on NSCs seems to be a mirror image of those of miR-125b
on HF-SCs.
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