Abstract

During development of the vertebrate body axis, Hox genes are transcribed sequentially, in both time and space, following their relative positions within their genomic clusters. Analyses of animal genomes support the idea that Hox gene clustering is essential for coordinating the various times of gene activations. However, the eventual collinear ordering of the gene specific transcript domains in space does not always require genomic clustering. We analyzed these complex regulatory relationships by using mutant alleles at the mouse HoxD locus, including one that splits the cluster into two pieces. We show that both positive and negative regulatory influences, located on either side of the cluster, control an early phase of collinear expression in the trunk. Interestingly, this early phase does not systematically impact upon the subsequent expression patterns along the main body axis, indicating that the mechanism underlying temporal collinearity is distinct from those acting during the second phase. We discuss the potential functions and evolutionary origins of these mechanisms, as well as their relationship with similar processes at work during limb development.

Highlights

  • Hox genes play essential roles in patterning during the development of metazoans

  • Murine Hoxd genes become activated in the most posterior part of the embryo between late embryonic day 7.75 (E7.75) for Hoxd1 and early E9 for Hoxd13. This temporal progression was proposed to be a molecular clock controlling the proper timing of axial specification by coordinating the rostral-caudal positions of the various expression boundaries [10]. While this view has found some support in studies of early limb patterning, where a strong correlation exists between the onset of Hox gene expression in the incipient limb bud and the extent of expression along the anterior to posterior axis [11], the situation in the developing major body axis appeared more complex

  • Interruption of Temporal Collinearity We evaluated whether the integrity of a Hox gene cluster is essential for temporal collinearity during early trunk development, by using a targeted inversion that splits the HoxD cluster into two smaller, independent gene clusters [21]

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Summary

Introduction

Hox genes play essential roles in patterning during the development of metazoans. In many species, they are found clustered in the genome, such as in vertebrates, which contain four Hox gene clusters (HoxA to HoxD), due to the additional two rounds of genome amplification that accompanied their emergence from early chordates. A precise spatial distribution of these transcription factors must be orchestrated so as to ensure proper specification These regionalized expression domains are in part controlled at a transcriptional level, by using an intrinsic property of the gene clusters, conserved from insects to vertebrates and referred to as spatial collinearity [4,5,6,7]: the order of genes along the chromosome correlates with their successive anterior limits of expression along the body axis. Murine Hoxd genes become activated in the most posterior part of the embryo between late embryonic day 7.75 (E7.75) for Hoxd and early E9 for Hoxd13 This temporal progression was proposed to be a molecular clock (the ‘Hox clock’) controlling the proper timing of axial specification by coordinating the rostral-caudal positions of the various expression boundaries [10]. While this view has found some support in studies of early limb patterning, where a strong correlation exists between the onset of Hox gene expression in the incipient limb bud and the extent of expression along the anterior to posterior axis [11], the situation in the developing major body axis appeared more complex

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