Tailored Hox gene transcription and the making of the thumb: Figure 1.

Abstract

As soon as the Hox genes were isolated in Drosophila and identified in mammals more than two decades ago, genetic and molecular data started to accumulate, suggesting a conserved function for these clustered genes in the specification of positional identity of rostro–caudal embryonic structures (Duboule and Dolle 1989; Graham et al. 1989). Temporal and spatial collinearity of expression of the Hox genes was shown to correlate with the anterior to posterior progression of development, with 3′ genes being expressed earlier and more anteriorly than successively more 5′ genes. Shortly after these discoveries, overlapping expression patterns of the 5′ subset of Hoxd genes in the developing mouse limb buds suggested that these genes were involved in patterning the limbs as well (Dolle et al. 1989). A strikingly high expression level of the last gene of the cluster, Hoxd13, in the genital bud and in the distal part of the limb buds opened the possibility that a “quantitative collinearity” might be playing a role in genital and limb development, obeying rules distinct from those of axial collinearity (Dolle and Duboule 1989; Dolle et al. 1991). The analysis of early and late phases of Hox gene expression in the chick limb bud further strengthened the suggestion that a “reversed,” 5′-nested Hox collinearity was at work at late stages in distal limb buds (Morgan and Tabin 1994; Nelson et al. 1996). The relationship between the two different types of collinearity was approached experimentally in the mouse, thanks to the design of a powerful genetic tool, the targeted meiotic recombination (Herault et al. 1998), making it possible to engineer rearrangements at will within the Hoxd cluster. It appeared that 5′-located Hoxd genes that display spatial and temporal collinear expression in the developing trunk and early limb bud undergo a subsequent distinct regulation in the distal part of the limbs at later stages (Zakany et al. 2004; Tarchini and Duboule 2006). The later phase of Hoxd expression modulates morphogenesis of the digital plate, distally extending the limb buds. This distal limb expression was found to depend on remote enhancers on the centromeric (5′) side of the HoxD cluster (Spitz et al. 2003). Information from comparative genome analysis recently shed additional light on the relationship between Hox expression and function along the axis and in the growing limbs, in the context of evolutionary developmental biology. Vertebrate Hox genes are arranged in much more condensed and organized clusters than their homologs in all other clades of the evolutionary tree (Duboule 2007). As compact clusters are conceivably more easily controlled in a coordinated way from distant enhancers, this may have provided an evolutionary opportunity for the recruitment of efficient regulatory regions from outside the HoxD cluster. The novel regulatory input would be at the origin of the late expression phase of Hoxd genes in the distal limb margin, in a suitable context to shape the vertebrate limb terminal elements, the digits (Duboule 2007; Freitas et al. 2007). In this issue of Genes & Development, Montavon et al. (2008) report on their quantification of the expression of the 5′ members of the HoxD cluster in normal and rearranged configurations, and on their design of a mathematical model of the regulatory circuit driving the late phase of Hoxd gene expression. They propose an additional, exquisite outcome of the quantitative regulation of the 5′ Hoxd genes: the ontogeny of a distinct morphology for digit 1, the thumb.