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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 ).
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