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Thus, when the HF-SCs were unable to downregulate miR-125b, the upper
ORS became hyperthickened with cells that appeared to be uncommitted
HF-SCs. Similarly, the entire process of lineage progression appeared to be
delayed when miR-125b could not be properly downregulated (
Zhang
et al
.,
2011
). The overall outcome was eventual baldness. Similarly, the SG progeni-
tors were expanded as a consequence of miR-125b overexpression, leading to
enlarged SGs.
Intriguingly, the maintenance of HF-SCs and SG progenitors appeared
to be intact, as upon withdrawal of doxycycline, the block to differentiation
was lifted and HFs and SGs were restored even after up to 4 months of
continuous miR-125b induction (
Zhang
et al
., 2011
). These observations
suggest a new model for the role of miRs in stem cells, namely, as a rheostat
to precisely govern their input into the differentiation program (
Fig. 7.4
B).
In
C. elegans
, one of lin-4's major targets is lin-28, which binds endoge-
nous primary let-7 transcripts and blocks its biogenesis into a miR.
Although let-7 is expressed by skin progenitors, lin-28 is not expressed
anywhere in the normal skin epithelium, suggesting that miR-125b/lin4 in
the HF-SCs must have other targets besides lin-28, and that let-7 must be
regulated by mechanisms that go beyond lin-28 (
Zhang
et al
., 2011
).
Microarray profiling of miR-125b-induced skin epithelium and subsequent
target analyzes revealed several downstream targets that could explain the
phenotype: the
VdR
gene encoding the vitamin D receptor, whose ablation
results in baldness (
Li
et al
., 1997; Palmer
et al
., 2008
) and the
Blimp1
gene
encoding a transcriptional repressor of
c-Myc
, whose ablation results in SG
enlargement (
Horsley
et al
., 2006
). Interestingly, both
VdR
and
Blimp1
have
been identified as miR-125b targets in other cell types and tissues
(
Gururajan
et al
., 2010; Malumbres
et al
., 2009; Mohri
et al
., 2009
). That
said, the skin phenotype of the miR-125b-induced mouse is complex, and
additional targets are likely to be involved. Future studies will be needed to
address these issues.
10. Delving Further into miR Functions in
Stem Cells: The Hematopoietic System
Hematopoietic stem cells (HSCs), with their well-defined cell
lineages, offer an ideal system to map the lineage-specific expression patterns
of miRs and decipher their roles in differentiation. In one of the earliest
studies of mammalian miRs, miR-181, miR-223, and miR-142 were all
found to be upregulated when bone marrow progenitor cells differentiate
toward B lymphocytes (
Chen
et al
., 2004
). Moreover, forced expression of
miR-181 in those progenitors enhanced B-lymphoid development at the
expense of T-lymphoid differentiation. In another important study, it was
