Biology Reference
In-Depth Information
complexity of predicted target specificities. The location of these miRNAs
within Hox clusters provides an extensive framework for predicting and
understanding their developmental patterns of expression which have now
been detailed in many model organisms (
Asli and Kessel, 2010
;
Bender,
2008
;
Kloosterman
et al
., 2006
;
Mansfield
et al
., 2004
;
Qiu
et al
., 2009
;
Ronshaugen
et al
., 2005
;
Stark
et al
., 2008
;
Woltering and Durston, 2006,
2008
;
Zhao
et al
., 2010
). This spatial information, coupled with the wealth
of data being generated by deep sequencing projects, has provided impor-
tant insight into the tissue restriction and relative expression levels of Hox-
embedded miRNAs.
Hox-embedded miRNAs are predicted to extensively, though by no
means exclusively, target protein-coding Hox mRNAs. Functional studies
that have been performed to date have borne this out, confirming
in vivo
Hox mRNA regulation by
miR-196
and
miR-10
in vertebrates and by
miR-
iab-4/8
in
Drosophila
(
Asli and Kessel, 2010
;
Bender, 2008
;
Hornstein
et al
.,
2005
;
McGlinn
et al
., 2009
;
Ronshaugen
et al
., 2005
;
Stark
et al
., 2008
;
Tyler
et al
., 2008
;
Woltering and Durston, 2008
).
In the following sections, we review current progress toward under-
standing the evolution of Hox-embedded miRNA families, on regulation
of their embryonic expression patterns, and on their patterning functions.
Hox genes are predicted targets of many other miRNAs, and conversely,
Hox-embedded miRNAs target many non-Hox transcripts; however, here,
we focus primarily on understanding the role of Hox-embedded miRNAs
in Hox mRNA regulation.
2. Genomic Organization and Evolution
2.1. Hox clusters
The Hox gene clusters arose via duplication and divergence of an ancestral
homeobox gene prior to the cnidarian-bilaterian split. The last common
bilaterian ancestor likely possessed at least eight clustered Hox genes (
Butts
et al
., 2008
;
Lemons and McGinnis, 2006
). Most extant bilaterians retained a
single cluster of 8-9 genes, although there have been lineage-specific
gene duplications, losses, and rearrangements. In chordates,
Abd-B-
class
genes expanded to
Hox9-13
in vertebrates (
Hox9-15
in cephalochordates).
Several whole-cluster duplications also occurred; the first was likely in stem
vertebrates, and a second in basal gnathostomes, generating four clusters,
Hoxa-d
(
Holland and Garcia-Fernandez, 1996
;
Prohaska and Stadler, 2004
;
Stadler
et al
., 2004
). An additional round of duplication and subsequent
loss generated 7-8 clusters in teleosts (
Amores
et al
., 1998
). Finally, 1-2
duplications occurred in the lineage leading to extant cyclostomes (lamprey
and hagfish) (
Force
et al
., 2002
;
Fried
et al
., 2003
;
Stadler
et al
., 2004
).
