Biology Reference
In-Depth Information
miR-1
in
C. elegans
:
miR-1
mutants ordinarily proceed through develop-
ment normally, but display developmental defects when containing muta-
tions that partially compromise either the general miRNA production
machinery or a range of other regulatory pathways (
Brenner
et al
., 2010
).
Taken together, the analysis of worms, flies, and zebrafish indicates that
miR-1
is not essential for myogenesis in these animals. A definitive determi-
nation of the requirement for
miR-1
family miRNAs in mouse muscle
development awaits the construction of
miR-1-1
/
miR-1-2
double mutants
as well as
miR-1-1
/
miR-1-2
/
miR-206
triple mutants.
Deletions of the cotranscribed partner of
miR-1-2
,
miR-133a-1
, as well
as its sibling
miR-133a-2
have also been reported (
Liu
et al
., 2008
). Deletion
of either
miR-133a-1
or
miR-133a-2
has no apparent effect on develop-
ment. However,
miR-133a-1
/
miR-133a-2
double mutants display a con-
stellation of phenotypes that are very similar to the
miR-1-2
single mutants
(
Liu
et al
., 2008
). Roughly half the
miR-133a-1
/
miR-133a-2
double mutant
mice die as late embryos or neonates with ventricular septum defects. Those
that survive display cardiomyocyte hyperplasia but normal skeletal muscles
formation and function. Gene expression analysis of
miR-133a-1
/
miR-
133a-2
double mutant hearts found a disproportionate increase in smooth
muscle genes regulated by SRF (
Liu
et al
., 2008
). This finding is consistent
with the
miR-1
/
miR-133
targets identified in zebrafish (
Mishima
et al
.,
2009
) and provides a mechanistic basis for the defects in heart morphology
displayed by the
miR-133a-1
/
miR-133a-2
double mutants. The similarity
between the
miR-133a-1
/
miR-133a-2
and
miR-1-2
mice is intriguing,
given the characterization of their opposing roles in cell culture (
Chen
et al
., 2006
). Understanding how bicistronic miRNAs can work together
in some contexts but antagonistically in others will be interesting.
3.2.2. miR-1/206 and let-7 in neuromuscular junctions
Genetic analyses have identified postdevelopmental roles for
miR-1/206
family members in neuromuscular junction (NMJ) function in both worms
(
Simon
et al
., 2008
) and mice (
Williams
et al
., 2009
), and a developmental
role for the
let-7
miRNA in NMJ formation in flies (
Caygill and Johnston,
2008
;
Sokol
et al
., 2008
). Muscle development in
miR-1
mutant worms
(
Simon
et al
., 2008
) and
miR-206
mutant mice (
Williams
et al
., 2009
)
proceed normally, but each of these mutant strains displays defective muscle
behavior in response to external perturbation. Pharmacological treatments
of
miR-1
mutant worms, for example, identified a role for
miR-1
both in
controlling the postsynaptic activity of nicotinic acetylcholine receptors as
well as in the presynaptic release of acetylcholine (
Simon
et al
., 2008
).
Double mutant and transgenic experiments indicate that
miR-1
performs
its postsynaptic role by directly regulating the levels of nicotinic acetylcho-
line receptor subunits in muscle cells. Similarly,
miR-1
mediates its presyn-
aptic role by directly regulating the MEF2 transcription factor, which
