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of RNA processing and translocation steps to yield mature miRNAs
within the cytoplasm (reviewed in
Carthew and Sontheimer, 2009
).
There, miRNAs bind to target mRNAs generally, although not exclu-
sively, in the 3
0
UTR, which directs the RNA-induced silencing complex
(RISC) to the mRNA. Almost all animal miRNAs bind their target
sequence with imperfect complementarity, and the importance of partic-
ular nucleotides in mediating this interaction has become evident
(
Brennecke
et al
., 2005
;
Grimson
et al
., 2007
;
Lim
et al
., 2005
). The
“seed” sequence is critical for specificity and consists of Watson-Crick
pairing between nt 2-7, with an additional complementary base at nt 8 or
an A at nt 1. This interaction reduces target protein levels by multiple
mechanisms leading to translational inhibition, and potentially to a large
extent through mRNA destabilization (
Baek
et al
., 2008
;
Carthew and
Sontheimer, 2009
;
Guo
et al
., 2010
; reviewed in
Carthew and
Sontheimer, 2009
). One important exception is the interaction between
miR-196
and its target gene
Hoxb-8
. Here, the miRNA binds with near-
perfect complementarity, initiating endonucleolytic cleavage and degrada-
tion of the mRNA (
Mansfield
et al
., 2004
;
Yekta
et al
., 2004
).
miRNAs have emerged recently as important regulators of embryonic
development. Some of the best-studied animal miRNAs are thought to
help regulate cell lineage progression and/or maintain transcription pro-
files of differentiated cell types, by targeting suites of mRNAs associated
with progenitor cell states and by fine-tuning levels of coexpressed tran-
scripts (reviewed in
Takacs and Giraldez, 2011
). More generally, there has
been recent suggestion that, through subtle but extensive regulation of
mRNA targets both outside and within of targets' expression domains,
miRNAs may function to canalize developmental programs, buffering
against stochastic variations in transcription and raising the threshold of
gene expression required to alter morphology (reviewed in
Hornstein and
Shomron, 2006
). The extent to which miRNA regulation contributes to
coordinated Hox output is under intense investigation following the
observation that several highly conserved miRNA families are embedded
within Hox clusters (
Aravin
et al
., 2003
;
Lagos-Quintana
et al
., 2001,
2003
;
Lim
et al
., 2003
;
Ronshaugen
et al
., 2005
;
Yekta
et al
., 2004
). For
example,
miR-10
resides in almost all taxa between
Hox4
and
5
paralogs
and arose in early bilaterians.
miR-196
is located between
Hox9
and
10
paralogs and is specific to vertebrates and urochordates. In arthropods,
miR-iab4/8
is located at the analogous position to
miR-196
and interest-
ingly, may have a similar function.
Hox-embedded miRNA families have a dynamic evolutionary history
that often parallels that of Hox clusters themselves, with duplication, gene
loss, and gene transposition occurring in various lineages (
Fig. 2.1
). Further,
lineage-specific and developmentally regulated posttranscriptional variation
including arm switching, seed shifting, and RNA editing increases the
