Biology Reference
In-Depth Information
availability of sequence information from evolutionarily distant species
indicates a conserved benefit to particular locations for Hox-embedded
miRNAs since there have been several independent events positioning a
miRNA upstream of
Hox8
or
9
paralogs. Further, the position of
miR-10
between
Hox4
and
Hox5
is almost universally conserved. Why are these
miRNAs positioned here? It is perhaps notable that, as discussed above, they
bracket groups of Hox genes that pattern distinct morphological regions
along the body axis. At least in vertebrates, morphological transition points
appear especially sensitive to quantitative changes in Hox protein and might
require miRNA regulation. In insects, both miRNA families bracket and
predominantly regulate central Hox genes which control thoracic pattern-
ing, considered an evolutionary “ground state” developmental program
(reviewed in
Gehring
et al
., 2009
). This could be beneficial because more
recently evolved programs (anterior and posterior) may require robust
repression of central Hox genes to support neofunctionalization. In verte-
brates,
miR-10
and
miR-196
target predictions are more in line with roles in
reinforcing posterior prevalence (rather than only regulating central genes)
along the length of the body axis. However, blocking
miR-196
in chick
does lead to posterior homeotic transformations of cervical toward thoracic
(also ground state) segments and anterior expansion of
Hoxb-8
expression.
When overexpressed, these miRNAs can have quite dramatic conse-
quences for developmental programs (e.g.,
Drosophila miR-iab-4
/
8
, and to a
lesser extent zebrafish
miR-10
) indicating the
in vivo
context for regulation
exists, in terms of 3
0
UTR availability. It is therefore surprising that loss-of-
function studies to date have revealed subtle, if any, defects. These data lend
support to accumulating evidence suggesting many miRNAs do not drive
certain developmental processes but may buffer genetic systems providing
robustness of output (
Li
et al
., 2009
;
Staton
et al
., 2011
). Given the many
levels of Hox network regulation, it is plausible that the molecular changes
occurring following loss of miRNAs which would otherwise lead to phe-
notypic changes are being compensated for by other mechanisms. For a
genetic network as fundamentally critical to embryogenesis as the Hox
network, it is clear to see the importance of redundant and/or fine-scale
regulatory mechanisms to limit potentially detrimental effects of gene
expression fluctuations or misregulation.
Why have Hox-embedded miRNAs been evolutionarily maintained?
These miRNAs clearly contribute to shaping Hox expression domains
particularly at their posterior boundaries and likely synergize with other
regulatory mechanisms to ensure timely clearance of unwanted transcripts.
In addition, there has been suggestion that these miRNAs may act to restrict
“transcriptional noise” that is generated as a byproduct of Hox clustering
(
Woltering and Durston, 2008
). While not essential, clustering of Hox
genes facilitates coordinated regulation. However, in some cases, this clus-
tering, and therefore the proximity of unshared as well as shared regulatory
elements, might also produce aberrant transcription of closely linked genes.
