Biology Reference
In-Depth Information
3.2.1. miR-1/206 and miR-133 families in muscle development
As described above, there are three bicistronic miRNA clusters in the
mouse genome that each encodes one member of the
miR-1
/
206
family
and one member of the
miR-133
family (
Chen
et al
., 2006
;
Liu
et al
., 2007
;
Rao
et al
., 2006
). Deletions of four of these six miRNAs have been
generated and analyzed to date, including
miR-1-2
and
miR-206
as well as
miR-133a-1
and
miR-133a-2
(
Liu
et al
., 2008
;
Williams
et al
., 2009
;
Zhao
et al
., 2007
). In each case, care was taken so that the expression of the
cotranscribed neighbor was not affected. While the elimination of
miR-206
seems to have no effect on cardiac and skeletal muscle development
(
Williams
et al
., 2009
),
miR-1-2
is required for heart development (
Zhao
et al
., 2007
): roughly half of the
miR-1-2
mutants die prior to adulthood and
display defects in the formation of the ventricular septum, which is the wall
that divides the left and right ventricles of the heart. This malformation is
indicative of abnormal heart morphogenesis and arises late during embryo-
genesis; histological analysis of early embryos indicates that initial heart
formation is normal. Surviving
miR-1-2
mutants have grossly normal
heart morphology but display a number of adult phenotypes including an
increase in cardiomyocyte number. Thus, removal of one of the two copies
of
miR-1
leads to clear defects in muscle development and function (
Zhao
et al
., 2007
) and indicates that the extremely high expression of
miR-1
in the
heart is functionally significant (
Rao
et al
., 2009
).
Although
miR-1-2
mutants display no apparent defects in mesoderm
determination, embryonic myoblast fate specification, or skeletal muscle
myogenesis, involvement in these processes might be compensated for by
miR-1-1
as well as the closely related
miR-206
. However, genetic depletion
of the single copy of
miR-1
in both flies and worms as well as of MZ
dicer
in
zebrafish indicates that
miR-1
is not required for muscle formation (
Giraldez
et al
., 2005
;
Simon
et al
., 2008
;
Sokol and Ambros, 2005
). In
Drosophila
mutants in which a 57-bp region containing the
miR-1
21-mer has specifi-
cally been deleted, for example, the muscle system forms and is morpholog-
ically and functionally normal (
Sokol and Ambros, 2005
). Indeed,
80% of
miR-1
mutant embryos hatch into motile larvae with normal body wall
contraction and heart rates. Feeding triggers their death, however, indicat-
ing that
miR-1
is required for postmitotic growth of larval muscle. Interest-
ingly, mutants homozygous for a 31-kbp deletion that removed
miR-1
and
surrounding sequences displayed a much stronger muscle phenotype:
66%
of these mutants die during embryogenesis and display defects in cardiac and
somitic muscle patterning (
Kwon
et al
., 2005
). The difference between the
phenotypes of these two
miR-1
alleles suggests that the
miR-1
phenotype
might be very sensitive to genetic background, or alternatively that some of
the noncoding transcripts neighboring
miR-1
and detected by profiling
microarrays may coordinately control muscle formation along with
miR-1
(
Graveley
et al
., 2011
). Such scenarios are consistent with the analysis of
