Biomedical Engineering Reference
In-Depth Information
other types of stress these miRNA-repressed mRNAs were able to come out of
P-bodies (in a ELAVL1-dependent mechanism) and get recruited to polysomes
(Huang et al., 2007).
3 Stem Cells and miRNA
Metazoans depend on three classes of stem cells, namely, embryonic stem
cells, adult stem cells, and adult germline stem cells, for their early develop-
ment and the maintenance of organs/tissues during adulthood. Stem cells have
the unique property of self-renewal, defined as indefinite propagation, while
retaining their potential to differentiate into multiple lineages when appro-
priate signals are provided both in vitro and in vivo. Their ''stemness'' is
maintained through a series of intricate mechanisms, including a network of
transcription factors, an internal epigenetic program, and extrinsic signals
from the surrounding niche. Since their discovery in C. elegans, where miR-
NAs were shown to play an important role in development, miRNAs have
been shown to play a critical role in the maintenance of self-renewing stem
cells and in their ability to differentiate into various lineages (Cheng et al.,
2005b; Forstemann et al., 2005; Hatfield et al., 2005; Houbaviy et al., 2003;
Kanellopoulou et al., 2005; Kuwabara et al., 2004; Lee et al., 2005; Murchison
et al., 2005; Suh et al., 2004; Tang et al., 2006; Yang et al., 2001).
3.1 Embryonic Stem Cells and miRNA
Embryonic stem cells are a distinct set of pluripotent stem cells from the early
embryonic developmental stage (from the inner cell mass of blastocysts). They
can be propagated indefinitely while maintaining their plasticity under in vitro
conditions and differentiate into all three germ layers of a developing animal.
The importance of miRNAs in normal development was illustrated when
disruption of Dicer-1 in D. melanogaster and of Dicer in mice led to embryonic
lethality at day 7.5 (Bernstein et al., 2003; Kloosterman and Plasterk, 2006;
Murchison et al., 2005; Wienholds and Plasterk, 2005; Yang et al., 2005). A
close study of these abnormal embryos showed a loss of pluripotent stem cells
(Bernstein et al., 2003). When Dicer function was disrupted by gene targeting in
mouse ES cells, it resulted in ESCs with defective miRNA processing and
compromised differentiation capabilities (Bernstein et al., 2003; Kanellopoulou
et al., 2005). These cells also elucidated a role for centromeric repeat-specific
small RNAs, whose expression is dependent on Dicer function, in the main-
tenance of the heterochromatin status of these repeats. Dicer deletion/ablation
in specific tissues also suggests the critical role of miRNA biogenesis in their
development and differentiation. Conditional Dicer-knockout mice in which
the Dicer gene was deleted specifically in the primordial germ cells (PGCs)
and spermatogonia exhibited reduced proliferation resulting in retarded
