MicroRNAs in the Hox network: an apparent link to posterior prevalence

Abstract

Homeobox (Hox) transcription factors confer anterior-posterior (AP) axial coordinates to vertebrate embryos. Hox genes are found in clusters that also contain genes for microRNAs (miRNAs). Our analysis of predicted miRNA targets indicates that Hox cluster-embedded miRNAs preferentially target Hox mRNAs. Moreover, the presumed Hox target genes are predominantly situated on the 3' side of each Hox miRNA locus. These results suggest that Hox miRNAs help repress more anterior programmes, thereby reinforcing posterior prevalence, which is the hierarchical dominance of posterior over anterior Hox gene function that is observed in bilaterians. In this way, miRNA-mediated regulation seems to recapitulate interactions at other levels of gene expression, some more ancestral, within a network under stabilizing selection.

Figure 1. Predicted repression of Hox genes by Hox microRnAs

a | The mouse Hox clusters. Blue and green lines indicate repression by the microRNAs (miRNAs) miR-10 and miR-196, respectively. All targets are conserved in humans, except Hoxd1 and Hoxa4 (dashed line). b | A model for the role of Hox miRNAs in modulating the Hox code. Hox miRNAs are placed within a scheme of embryonic development along a segmented anterior–posterior axis. The most anterior segment displays the default developmental state that is specified in the absence of Hox expression. This state is modified towards more posterior fates by miRNAs that dampen the activity of Hox genes that are situated 3′ of the miRNA locus. The second most anterior segment is the anterior boundary of expression for the Hox genes that are situated 3′ of the miRNA locus, which specify earlier and more anterior fates. Hox miRNAs dampen the posterior expression of their 3′ Hox targets. In the more posterior domains, they act in parallel with 5′ Hox genes to reinforce the hierarchy of 5′ Hox function. Within the most posterior domains of Hox miRNA expression, the miRNAs provide fail-safe repression of aberrant or low-level and experimentally undetectable transcription. Alternatively, they might linger as stable species following the clearance of 3′ Hox targets. The targets are generally expressed prior to the miRNAs, and thus the miRNA-mediated modulation of expression domains also has a temporal dimension (not shown).