Biology Reference
In-Depth Information
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
Search WWH ::




Custom Search