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presumably activates a retrograde signal that culminates in changes in
acetylcholine release by innervating neurons.
Like worm
miR-1
, mouse
miR-206
is also involved in retrograde signal-
ing, in its case to promote the formation of new NMJs after denervation
(
Williams
et al
., 2009
). Expression of
miR-206
is sharply upregulated in
response to denervation, and the initial rate of reinnervation by motor axons
is delayed in
miR-206
mutants relative to wild type. Roughly 90% of both
wild-type and
miR-206
-deficient muscles are reinnervated after 8 weeks,
though, suggesting a compensatory mechanism that may involve
miR-206
's
neighbor
miR-133b
, which is also robustly activated in response to dener-
vation. Since
miR-206
apparently promotes retrograde signaling by mod-
ulating FGF signaling through its direct target
hdac4
, it will be interesting to
see whether
miR-133b
also promotes reinnervation after injury or is impli-
cated in FGF signaling.
While the muscle-specific
miR-1
/
206
family is involved in postdevelop-
mental NMJs, the
let-7
miRNA is required for the formation of NMJs
during development (
Caygill and Johnston, 2008
;
Sokol
et al
., 2008
).
Elimination of the
let-7
miRNA results in a reduction in NMJ length and
a corresponding decrease in muscle size. The
let-7
mutant phenotype
mimics the effects of denervation of wild-type muscle and suggests that
let-7
may function in neurons and/or muscles. Either way, it presumably
mediates its affect via direct control of the
abrupt
transcription factor (
Caygill
and Johnston, 2008
).
3.2.3. miR-143 and miR-145 in smooth muscle
Like the
miR-1
and
miR-133
miRNAs,
miR-143
and
miR-145
are also
encoded in a bicistronic locus (
Cordes
et al
., 2009
). This one is present in
single copy in the mouse genome and is expressed in the heart during early
embryogenesis (E7.5-E16.5) (
Cordes
et al
., 2009
;
Xin
et al
., 2009
). In adult
mice, though, expression of the
miR-143
/
miR-145
locus is confined to
vascular and visceral smooth muscle cells (
Cordes
et al
., 2009
;
Xin
et al
.,
2009
). Genetic deletion of
miR-143
and
miR-145
, either alone or together,
has no effect on viability, cardiac structure, or cardiac gene expression
(
Boettger
et al
., 2009
;
Elia
et al
., 2009
;
Xin
et al
., 2009
). However, the smooth
muscle layer of the aorta and other arteries of the
miR-145
single mutants as
well as the
miR-143
/
miR-145
double mutants is thinner, due to a reduction
in the width of smoothmuscle cells (
Boettger
et al
., 2009
;
Elia
et al
., 2009
;
Xin
et al
., 2009
). Thus, removal of
miR-143
/
miR-145
affects the morphology
rather than the development or differentiation of smooth muscle cells,
presumably due to the direct regulation of cytoskeletal components by
these miRNAs. While the developmental role of these miRNAs is relatively
mild, they play critical roles in mediating vascular smooth muscle cell pro-
grams in response to injury and may target additional mRNAs in this context
(
Boettger
et al
., 2009
;
Elia
et al
., 2009
;
Xin
et al
., 2009
).