Biology Reference
In-Depth Information
whole family might not cause the severe developmental defects in cell fate
specification that would be expected from ablation of a gene encoding a
master regulator. However, when these mutant mice are subject to physio-
logical stresses like injury or DNA damage, significant phenotypes surface
(reviewed by
Leung and Sharp, 2010; Liu and Olson, 2010
). These obser-
vations are yet further indicators that miR-mediated regulation functions by
fine-tuning responses and reinforcing the robustness of biological systems
that may not be readily manifested in a well-maintained laboratory condi-
tion (reviewed by
Herranz and Cohen, 2010
). It is worth noting that
because of the central role of stem cells during the development and
homeostasis of adult tissues, dysregulation in stem cells could be magnified
and manifested as defects in their differentiated daughters. This illustrates a
critical need for the future to investigate how stress signals regulate miR
expression and how miR-mediated regulation, in turn, balances the output
of gene expression and protects stem cells from the various and diverse
stresses that they encounter throughout the life.
A second key issue to address will be how a single miR can execute its
physiological function by regulating its targets. Directly related to this is the
question whether a single miR can perform different roles when placed in
distinct cellular contexts. As miR functions in mammalian stem cells begin
to unfold, some of the most challenging questions to be answered will be
which mRNAs are targeted by a specific miR and which of its many targets
are key in a given cellular context.
A third key area to be addressed in the future is the question of how
miR-mediated regulation integrates with other regulatory mechanisms, for
example, transcriptional regulation, to modulate stem cell fate. Although
biologists now appreciate the importance of the regulatory layer provided
by miRs, the interactions between the miR pathway and other regulatory
mechanisms must be elucidated to fully understand how miRs work.
Further, it will be important to unveil the characteristics of the miR
pathway that are distinct from other mechanisms such as cellular context-
dependent function.
Finally, miR's functions in human diseases especially cancer are particu-
larly intriguing. Because miRs' functions are highly dependent upon local
mRNA content, it is conceivable that their functions in cancer cells could
dramatically differ from their functions during normal development. Thus,
characterization of individual miRs' roles at different stage of tumorigenesis
will be important to understand the underlying biology of tumor develop-
ment. In particular, because of the central roles of cancer stem cells in tumor
development and relapse, it is critical to focus on miR-mediated regulation in
these cells. Answers to these fascinating questions are certainly not only going
to provide significant new insights into miR functions but also point to new
directions to utilize and target miRs in the manipulation of stem cells for
regenerative medicine as well as in the development of cancer therapies.
