Biomedical Engineering Reference
In-Depth Information
spermatogenesis (Hayashi et al., 2008). A recent report also showed that Dicer
deletion in the mesenchyme of the Mullerian duct in the female reproductive
tract caused sterility, suggesting that miRNA biogenesis is required for proper
Mullerian duct differentiation (Nagaraja et al., 2008). Conditional inactivation
of Dicer in the retina led to progressive degeneration, and the animals were
unable to respond to light, suggesting that miRNAs are involved in retinal
neurodegenerative disorders (Damiani et al., 2008). Selective inactivation of
Dicer in the forebrain neurons caused cellular and tissue morphogenesis defects,
suggesting a role for miRNA in neurological disorders (Davis et al., 2008). It
would be interesting to look at Dicer ablation selectively in neural stem/pro-
genitor populations in embryos and adults. Deleting Dicer in different tissues,
such as the heart and B and T cells, also indicates the importance of miRNA at
multiple layers (Chen et al., 2008; Koralov et al., 2008).
Another conditional mutation study where DGCR8 was mutated showed a
decreased differentiation potential in the resulting mutant ES cells (Wang et al.,
2007). Results from these mutation studies clearly showed a critical role for
miRNAs in the differentiation of ES cells. Cloning efforts to identify ES cell-
specific miRNA revealed that six miRNAs, miR-290-295, are specifically
expressed in ES cells and could be involved in the maintenance of pluripotency
(Houbaviy et al., 2003), as their expression levels decreased significantly upon
onset of differentiation. A similar study where miRNAs specific for human
ESCs were cloned also identified two clusters of miRNAs (miR-371, -372, -373,
and -373* on chromosome 19 and miR-302, -302b*, -302c, -302c*, -302a,
-302a*, -302d, and 367 on chromosome 4) and showed that expression of
these miRNAs was down-regulated upon differentiation (Suh et al., 2004).
The presence of these ES cell-specific miRNAs in conserved clusters may
perhaps make their coordinated expression and repression based on cellular
intrinsic or extrinsic cues possible. There is evidence that these miRNAs do, in
fact, better reflect ES cell status compared to expression levels of Oct4 mRNA
(Palmieri et al., 1994; Yeom et al., 2006). miR-302 is noteworthy, as it is
expressed in mouse ESCs, hESCs, and human embryonic carcinoma cells.
As evidenced by the loss-of-function experiments with Dicer and DGCR8, a
more direct role for miRNA is perhaps in the regulation/facilitation of differ-
entiation of ES cells. There are, in fact, a set of miRNAs whose expression goes
up when ES cells start to differentiate (e.g., miR-21) (Houbaviy et al., 2003;
Singh et al., 2008). It is well established now that the pluripotency of ESCs is
preserved by an interconnected network of transcription factors. A network of
miRNAs responsible for maintaining the identity of a specific cell type has been
documented (Johnston et al., 2005; Tsang et al., 2007). It is apparent now that
miRNAs can act as another layer of factors that can influence gene expression
patterns. It will be interesting to see how the inter-connection between the
transcription factor and miRNA networks regulates the self-renewal, differen-
tiation/lineage potential of ESCs. In one such study, the network of core
transcription factors (Oct4, Sox2, Nanog, and TCF3) known to maintain
embryonic stem cells in a self-renewing pluripotent state was also shown to
