Hox genes and regional patterning of the vertebrate body plan

Abstract

Several decades have passed since the discovery of Hox genes in the fruit fly Drosophila melanogaster. Their unique ability to regulate morphologies along the anteroposterior (AP) axis (Lewis, 1978) earned them well-deserved attention as important regulators of embryonic development. Phenotypes due to loss- and gain-of-function mutations in mouse Hox genes have revealed that the spatio-temporally controlled expression of these genes is critical for the correct morphogenesis of embryonic axial structures. Here, we review recent novel insight into the modalities of Hox protein function in imparting specific identity to anatomical regions of the vertebral column, and in controlling the emergence of these tissues concomitantly with providing them with axial identity. The control of these functions must have been intimately linked to the shaping of the body plan during evolution.

Fig. 1

Regional patterning of the axial skeleton by Hox paralog groups 6 and 10. Skeletal preparations showing the effects of global inactivation (LOF) or of ectopic activation (GOF) of genes in the paralogous Hox groups 6 (red labels) and 10 (green labels). HoxPG10 genes have rib blocking activity as shown by the ectopic ribs observed in the lumbar area of mice with complete inactivation of this paralog group (D) and by the complete absence of ribs (green asterisk) after precocious activation of Hoxa10 in the presomitic mesoderm (C). HoxPG6 genes are able to induce ectopic ribs at cervical (R* in F) and lumbar (G) levels. Complete inactivation of HoxPG6 genes (E) results in smaller rib cages and loss of specific ribs (first rib in this specimen is attached to the second thoracic vertebra, T2), indicating that other genes must also cooperate in the rib-inducing process. A schematic representation of the Hox clusters is shown for reference. Skeletons of wild type embryos are shown in A and B. The lumbar and sacral domains, the position of the first thoracic (T1), last thoracic (T13), and first lumbar (yellow asterisks) vertebrae is indicated for reference.

Fig. 2

Cdx and central Hox genes are expressed in the primitive streak area, where the progenitors for axial tissues for trunk and tail reside (see references in the text). Expression of Cdx2 and Hoxb8 is shown on the left at E7.5 (Head fold stage). Axial tissues generated by these areas is schematically indicated in purple on the E9.5 embryo on the right.

Fig. 3

Axial skeleton of new born mice upon partial loss-of-function of Cdx genes and upon precocious HoxPG13 expression (A–E) and schematic representation of positive and negative regulators of axial extension before and after the trunk-tail transition (F). A, Cdx loss-of-function mutations (loss of one allele of Cdx2 and of both alleles of Cdx4) arrest axial extension prematurely. B, Wild type. C, Gain of function of the central Hox gene Hoxb8 partially rescues axial extension in Cdx mutants. D, Hoxc13 early gain of function leads to posterior axial truncation. E, Posterior activation of the canonical Wnt pathway by Lef1 constitutive expression partially rescues axial elongation in Cdx mutants. The posterior axial skeleton of new borns is shown with anterior on the left. See text for more details. F, Schematic representation of axial extension of trunk and tail between early somite stage (E8.0, X axis) and the end of posterior extension by tissue addition (E13.5). Shown are positive (“Central” Hox genes, and Cdx genes), and negative (HoxPG13) regulators of axial extension, and some of the effectors of axial growth between developmental stages E8.0 and E13.5. Expression levels (not to scale) are schematically indicated in the Y dimension. In green, growth stimulatory central Hox and Cdx expression, with Wnt signaling (blue) and RA clearance (orange) showing a parallel course. In red, growth inhibitory HoxPG13 expression. Decrease of axial growth stimulation and increase of inhibition correspond to the trunk-tail transition (around E10.5).