Biology Reference
In-Depth Information
a handful of muscle miRNAs whose expression is posttranscriptionally
regulated. Such posttranscriptional control provides a mechanism to rapidly
increase or decrease the amount of functional miRNAs in a cell, ensuring
rapid transitions in miRNA expression during myogenesis as well as in
postmitotic muscle cells. The functional significance of this regulation
during muscle development has yet to be reported, however.
2.5. mRNA targets of muscle miRNAs
Muscle miRNAs target a diverse set of mRNAs, including transmembrane
receptors, ion channels, cytoskeleton components, transcription factors, and
epigenetic enzymes. Of particular interest are the targeting issues raised by
the bicistronic organization of sequence divergent muscle miRNAs. Some
cotranscribed muscle miRNAs, like mouse
miR-143
and
miR-145
, cotarget
an overlapping set of mRNAs: reporter assays indicate that 3
0
UTRs of at
least five genes contain functional binding sites for both
miR-143
and
miR-
145
, including
klf4
,
klf5
,
adducin3
,
ssh2
, and
mrtf-B
(
Xin
et al
., 2009
). In
contrast, other cotranscribed miRNAs, like mouse
miR-1
and
miR-133
,
regulate largely nonoverlapping sets of mRNA targets. This conclusion is
supported by the fact that there is little overlap in the sets of mRNAs that are
misregulated in either
miR-1
or
miR-133
mutant tissue as detected by
microarray analysis (
Liu
et al
., 2008
;
Mishima
et al
., 2009
;
Shkumatava
et al
., 2009
;
Zhao
et al
., 2007
). Further, with the exception of one recently
analyzed 3
0
UTR (
Vo
et al
., 2010
), most characterized 3
0
UTRs contain
binding sites for either
miR-1
or
miR-133
but not both (
Boutz
et al
.,
2007
;
Chen
et al
., 2006
;
Ikeda
et al
., 2009
;
Li
et al
., 2010
;
Liu
et al
., 2008
;
Zhao
et al
., 2005, 2007
). Indeed,
miR-1
and
miR-133
have opposing
functions in C2C12 cells, with
miR-1
favoring differentiation by inhibiting
myoblast proliferation and
miR-133
suppressing differentiation by promot-
ing myoblast proliferation (
Chen
et al
., 2006
). Collectively, the analysis of
the
miR-143/miR-145
and
miR-1/miR-133
clusters suggests that cotran-
scribed miRNA clusters use differing targeting strategies and can target
either distinct or overlapping sets of mRNAs. The specific targets of a
number of other muscle miRNAs have been identified and will be discussed
below in reference to the miRNA mutant phenotype.
3. Functional Analysis of miRNAs During
Muscle Development
miRNA function can be determined by analyzing the consequences of
eliminating individual miRNAs on a case-by-case basis. Alternatively, the
consequences of depleting many miRNAs at once can be assayed by
