QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online June 8, 2005
doi: 10.1242/10.1242/dev.01897

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deschamps, J. Articles by van Nes, J. Search for Related Content PubMed PubMed Citation Articles by Deschamps, J. Articles by van Nes, J.

Developmental regulation of the Hox genes during axial morphogenesis in the mouse

Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands

View larger version (30K): [in a new window]   Fig. 1. Mouse Hox genes and their early temporal and spatial colinearity of expression. (A) The four Hox clusters (a to d). Hox genes with the same number (1 to 13) are called paralogs. Three paralog groups are shown (2, 4 and 9) in colour to illustrate the early temporal co-linearity of their expression, as shown in B. (B) Mouse embryos at: embryonic day (E) 7.2, late streak (LS) stage; E7.5, neural plate (NP) stage; and E7.7, head fold (HF) stage. (C) An E10.5 embryo, showing the spatial co-linearity of Hox gene expression. Hox2 paralogs begin to be expressed earlier, and Hox4 and Hox9 paralogs progressively later, in the posterior part of the primitive streak (ps, indicated by a grey line on the posterior side of the embryos in B). At E10.5, the expression domains of the 3' genes extend to more anterior positions than that of the more 5' genes. For each gene, the expression boundary is more anterior in the nervous system than in the mesoderm. mes, mesoderm; nt, neural tube. Actual widths of embryos at widest point: LS, 0.26 mm; NP, 0.44 mm; HF, 0.60 mm; E10.5, 4.1 mm.

View larger version (46K): [in a new window]   Fig. 2. Regulation of Hox gene expression throughout mouse embryogenesis. Expression of a 3' Hox gene, Hoxb1 (red), and of a 5' Hox gene, Hoxb8 (blue), at different developmental stages in mouse embryos. Posterior (P) is towards the left of the E10.5 embryo, owing to axial rotation, which mouse embryos undergo between E8.5 and E9.0. (A) E7.2, late primitive streak stage embryo, with the primitive streak (grey) reaching the node at the distal tip of the embryo. The red arrow shows the direction of the anterior expansion of the Hoxb1 expression domain. (B) E7.7, late head fold stage embryo, showing a maximally extended Hoxb1 expression domain (red) and an early expression field for Hoxb8 (in blue overlaying Hoxb1 expression). The blue arrow indicates the anteriorwards spread of the Hoxb8 expression domain; the orange line indicates retinoic acid (RA) in the mesoderm. (C) E8.0, five-somite stage embryo; the remnant of the primitive streak is shown in black medioposteriorly, with the node region at its anterior end. White circle indicates posterior stem cell zone. (D) E10.5 embryo; the remnant of the primitive streak is in the tailbud. Hoxb1 expression is downregulated and remains strong in rhombomere 4 anteriorly, and in the tailbud posteriorly. Hoxb8 expression is about to be induced by RA to extend rostrally into the posterior hindbrain (blue arrow). The role of Wnt and Fgf at the early stages (A,B) is assumed, but not definitively documented. See Fig. 8 for more detail on the role of the early locus enhancer, and Fig. 7 for that of the chromatin events. PSM, presomitic mesoderm. Green triangle indicates posterior-to-anterior Fgf and Wnt gradients. trxG and PcG, trithorax group and polycomb group protein complexes, which activate and repress Hox gene expression, respectively. Scale bars: 100 µm for A-C; 75 µm for D.

View larger version (41K): [in a new window]   Fig. 3. Rostral progression of Hox expression through the primitive streak region. The rostrally extending expression domain (purple) of a Hox gene (from the middle of a Hox cluster) in the posterior region of an E7.7 presomitic mouse embryo (anterior is towards the top). This Hox expression domain encompasses the area where cells emerge from the primitive streak and from the axial stem cell zone (see black arrows). It also crosses the posterior region of the axis, which is undergoing morphogenesis. Extra-embryonic mesoderm is produced from the posterior levels of the streak. Lateral plate and paraxial mesoderm emerge from more anterior levels. The approximate position of the axial stem cells is shown (yellow). The descendants of these stem cells contribute to the extending paraxial mesoderm and neural plate (black arrows). The node produces axial mesoderm (notochord), endoderm and the ventral midline of the neural plate (not shown). Extra-embryonic mesoderm production is indicated for the sake of completeness, although it has stopped by this stage.

View larger version (35K): [in a new window]   Fig. 4. Signalling molecules that affect Hox gene expression along the AP axis. An E8.5 (10 pairs of somites) stage mouse embryo, showing the hindbrain and spinal cord in the neural tube, and the occipital and trunk somites in the paraxial mesoderm. The distribution of RA is indicated in blue. RA is synthesized by Raldh2 in the somites. Anteriorly, RA diffuses into the hindbrain, where the Hox genes are differentially sensitive to RA. For example, rhombomeres (r) 3 and 4, where RA concentration is low, express only the most 3' Hox genes; r6 to r8 express the 3' plus more 5' Hox genes. Posteriorly to somite levels, the concentration of diffusing RA decreases more sharply because of the activity of a RA-degrading enzyme, Cyp26 (see red double-headed arrow, which also shows the extent of the presomitic mesoderm). Other signalling molecules present posteriorly are Wnt (not shown) and Fgf. Fgf signals (orange/yellow) are abundant around the node region and decrease gradually to fade out in the neurectoderm and in the mesoderm at the level of the last-formed somite. The node region and its nearby pool of stem cells (see Fig. 3) are exposed to high Fgf concentrations. The mesoderm and neurectoderm cells exposed to low Fgf concentrations are maturing. As the axis extends, `younger' cells come to experience this decreasing Fgf concentration.

View larger version (88K): [in a new window]   Fig. 5. Hox-like Cdx expression in embryos at gastrulation and early somite stages (A-C). Expression of the three Cdx genes in the primitive streak (ps) resembling that of 3' Hox genes (see Fig. 2). Cdx2 and Cdx4 are also expressed at the base of the allantois (all), and Cdx2 is expressed in the chorionic ectoderm (ch). Cdx2 is expressed earlier in the trophectoderm, where it is required for implantation (Chawengsaksophak et al., 1997; Strumpf et al., 2005). (D-F) The three Cdx genes are expressed strongly in posterior embryonic tissues (all three germ layers) at somite stages (anterior is towards the left). (D) The expression of Cdx1 extends to more anterior positions than that of Cdx2 (E) and Cdx4 (F). At later stages, Cdx genes are expressed in gene-specific patterns in the gut endoderm (not shown) (see Beck et al., 2000). Scale bars: 100 µm. ps, primitive streak.

View larger version (48K): [in a new window]   Fig. 6. Hox genes and the genetic network driving axial extension, mesoderm segmentation and AP patterning. Fgf, Wnt and RA signalling are functionally involved in axial extension (orange), somitogenesis (green) and AP patterning (purple). The relationship between the Hox genes, the Cdx genes, the segmentation genes of the Notch pathway and the three morphogenetic processes are indicated. Unbroken lines indicate established interactions; broken lines represent documented interactions that have not yet been established at the molecular level.

View larger version (23K): [in a new window]   Fig. 7. Histone marks and nuclear reorganisation during co-linear Hox activation. Schematic representation of histone marks and changes in the subnuclear position of Hox genes before (E6.5) or at the time of their first expression [E7.5 for Hoxb1 (b1), E8.5 for Hoxb4 (b4) and E9.5 for Hoxb9 (b9)]. The histone marks on histone H3, methylated lysine 4 (pink) and acetylated lysine 9 (purple), poise the genes for transcription from the moment the first Hox gene of the cluster (Hoxb1) is activated. Individual genes loop out of their chromatin territory (CT, grey line) at the time of their expression. Figure modified, with permission, from Chambeyron and Bickmore (Chambeyron and Bickmore, 2004), incorporating data from Chambeyron et al. (Chambeyron et al., 2005) and Rastegar et al. (Rastegar et al., 2004). The looping out of Hoxb4 is a personal extrapolation of the data on Hoxb1 and Hoxb9.

View larger version (14K): [in a new window]   Fig. 8. Global regulation of Hoxd gene cluster. (Left) The sequential activation of 3' to 5' Hoxd genes is shown from the hypothesised global early enhancer (EE) that mediates the temporally co-linear activation of the Hoxd genes along the main axis. The EE in the scheme corresponds to the ELCR (early limb control region) postulated by Zákány and colleagues (Zákány et al., 2004). (Right) The regulatory influence of the 5' global control region (GCR) on the Hoxd cluster and neighbouring genes in the digits (green) and neural tube (grey). A timescale is depicted below. The activation times of the Hoxd genes is shown for only three genes: Hoxd1 (yellow), Hoxd8 (orange) and Hoxd13 (brown). The action of the GCR is stronger on the most 5' gene Hoxd13 (thicker green arrow) than on Hoxd12 to Hoxd10. ins, insulator in neural tissues. Lnp, lunapark; Evx2, mouse even-skipped homolog 2.