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Finally, it is worth mentioning that miRs have also been implicated in
the regulation of stem cell aging. Hmga2, a key transcription factor for the
self-renewal of several types of stem cells, is highly expressed in fetal NSCs,
but its levels decline by more than 99% during the mouse's lifespan (
Nishino
et al
., 2008
). This decline in Hmga2 is accompanied by a reduction in self-
renewal capacity of NSCs and appears to be in part caused by a
30-fold
age-induced increase in the miR let-7b, known to target and inhibit Hmga2
expression (
Mayr
et al
., 2007; Nishino
et al
., 2008
). The specific disruption
of Hmga2 regulation with a truncated 3
0
UTR refractory to let-7 targeting
resulted in a significant rescue of the self-renewal capacity in an
in vitro
culture assay, supporting the causative role of let-7b in the downregulation
of Hmga2 expression (
Nishino
et al
., 2008
).
12. miR Function in Muscle Stem Cells
A recent study of skeletal muscle satellite cells provides another inter-
esting parallel to that of the skin stem cell lineages. Pax7 is a critical
transcription factor that is highly expressed in quiescent muscle stem (satel-
lite) cells and is required to maintain the stem cell population. Upon injury,
satellite stem cells are activated to repair the wound, and Pax7 is concomi-
tantly downregulated to allow these cells to progress to differentiate and
contribute to muscle regeneration. Both miR-1 and miR-206 target Pax7
mRNA and are markedly upregulated concomitant with downregulation of
Pax7 and satellite cell differentiation (
Chen
et al
., 2010
). Conversely,
specific inhibition of miR-1 and miR-206 by antagomirs delays Pax7
downregulation and interferes with the differentiation program (
Chen
et al
., 2010
). Overall, such findings are remarkably similar to the role of
miR-203 in regulating
in epidermal stem cells (
Yi
et al
., 2008
) and
together, point to the view that a number of somatic miRs expressed at the
transition between the stem cells and their differentiation lineage function in
fine-tuning the switch.
D
Np63
a
13. miR Function in Cancer Stem Cells
The role of miRs extends beyond normal development and is partic-
ularly intriguing in human cancer. The miR pathway is often dampened in
tumor cells (
Lu
et al
., 2005
). Indeed, reduced miR expression in Dicer
heterozygous animals has been shown a causative role in driving tumor-
igenesis and cellular transformation in several mouse models (
Kumar
et al
.,
2009
), and in the skin, the hyperproliferative epidermal phenotype is
suggestive of an increased sensitivity (
Andl
et al
., 2006
). In addition, the