Biology Reference
In-Depth Information
In this context, it is interesting to note extensive cotranscription of miR-
NAs with protein-coding Hox transcripts that at least in some cases are
found in areas where translation is repressed. Finally, the extent to which
Hox-embedded miRNAs “fine-tune” target gene expression in areas of
coexpression remains an open question. Many miRNA knockouts have
limited or no phenotypic alterations observed until the system is stressed
with environmental or genetic alterations (
Li
et al
., 2009
;
van Rooij
et al
.,
2007
;
Zhao
et al
., 2010
). Given the redundant nature of Hox network
regulation, compound mutant analysis (with non-miRNA-mediated regu-
latory mechanisms) may be required to reveal miRNA contribution.
Functional data for Hox-embedded miRNAs are still lacking in many
cases, notably in mammals. Not until all mouse knockouts are generated, a
complicated task due to presumed redundancy, will we know the full extent
to which these miRNAs contribute to Hox output in mammalian systems.
Finally, most Hox miRNA regulatory elements have yet to be defined, and
although there is accumulating evidence of complex posttranscriptional
processing, we know very little mechanistically regarding their transcrip-
tional and posttranscriptional regulation. While great strides have been
made, there are certainly exciting times ahead integrating miRNA function
within the classic Hox genetic hierarchies.
7.1. Note added in proof
Recent functional studies in zebrafish support a critical, nonredundant role
for
miR-196
in multiple developmental processes, often affecting quite
anterior structures (
He
et al
., 2011b
). Overexpression of
miR-196
induces
homeotic transformations of anterior vertebral structures along with a
striking inhibition of pectoral fin initiation, which in the latter case, appears
to be achieved via attenuation of RA signaling. Complementary gain- and
loss-of-function experiments indicate
miR-196
acts to restrict both pharyn-
geal arch number as well as vertebral number specifically of the rib-bearing
precaudal vertebrae. While these results indicate a conserved function of
miR-196
across species in suppressing rib formation, it is particularly inter-
esting to note that this is achieved by different mechanisms (homeotic
transformation in chick (
McGlinn
et al
., 2009
) and altered somite number
in zebrafish (
He
et al
., 2011b
)). Hox target gene expression was observed to
be dysregulated in mutant fish; however, the exact extent to which these
alterations contribute to altered skeletal patterning is currently unclear.
ACKNOWLEDGMENTS
We thank Cliff Tabin and Jessica Lehoczky for critical reading of the review. The Australian
Regenerative Medicine Institute at the Monash University is supported by grants from the
Australian Government and the State Government of Victoria, Australia. J. H. M.
is
supported in part by NSF IOS-0818223.
