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Hox genes control vertebrate body elongation by collinear Wnt repression.

Denans N, Iimura T, Pourquié O - Elife (2015)

Bottom Line: Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength.This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process.Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size.

View Article: PubMed Central - PubMed

Affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, University of Strasbourg, Illkirch, France.

ABSTRACT
In vertebrates, the total number of vertebrae is precisely defined. Vertebrae derive from embryonic somites that are continuously produced posteriorly from the presomitic mesoderm (PSM) during body formation. We show that in the chicken embryo, activation of posterior Hox genes (paralogs 9-13) in the tail-bud correlates with the slowing down of axis elongation. Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength. This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process. Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size. This ultimately brings the retinoic acid (RA)-producing segmented region in close vicinity to the tail bud, potentially accounting for the termination of segmentation and axis elongation.

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Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.Model representing the 3 phases (I, II, and III) of Hox actionin PSM precursors in the epiblast/tail-bud during body axis elongation.Anterior Hox genes (paralogs 1–9) are expressed duringphase I. They control cell ingression in a Pbx1-dependentmanner leading to the collinear positioning of Hox genesexpression domains in the anterior region of the embryo. NoHox genes are activated during phase II, allowing fastelongation of the embryonic axis. During phase III, posteriorHox genes (paralogs 9–13) are collinearly activatedin PSM precursors. Our data suggest that collinear activation of posteriorHox genes leads to repression of Wnt signaling and itstarget T/Brachyury, which progressively increases in strength.This results in a progressive arrest of cell ingression in the PSM, leading toa decrease in axis elongation rate. Since the velocity of somite formation isroughly constant, PSM size starts to decrease when elongation velocity becomesslower than that of somite formation. During this latter phase the control ofcell ingression by posterior Hox genes appears to beindependent of Pbx1.DOI:http://dx.doi.org/10.7554/eLife.04379.027
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fig11: Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.Model representing the 3 phases (I, II, and III) of Hox actionin PSM precursors in the epiblast/tail-bud during body axis elongation.Anterior Hox genes (paralogs 1–9) are expressed duringphase I. They control cell ingression in a Pbx1-dependentmanner leading to the collinear positioning of Hox genesexpression domains in the anterior region of the embryo. NoHox genes are activated during phase II, allowing fastelongation of the embryonic axis. During phase III, posteriorHox genes (paralogs 9–13) are collinearly activatedin PSM precursors. Our data suggest that collinear activation of posteriorHox genes leads to repression of Wnt signaling and itstarget T/Brachyury, which progressively increases in strength.This results in a progressive arrest of cell ingression in the PSM, leading toa decrease in axis elongation rate. Since the velocity of somite formation isroughly constant, PSM size starts to decrease when elongation velocity becomesslower than that of somite formation. During this latter phase the control ofcell ingression by posterior Hox genes appears to beindependent of Pbx1.DOI:http://dx.doi.org/10.7554/eLife.04379.027

Mentions: Genetic studies on mouse T mutants have shown that graded T activity is required forbody axis formation (Stott et al., 1993; Wilson and Beddington, 1997). Embryos withprogressively lower quantities of T exhibit more severe axis truncations (Stott et al., 1993). Similar graded truncationsare also observed for Wnt3a allelic series (Galceran et al., 1999), indicating that precise quantitativeregulation of this pathway is required for completion of body axis elongation.Repression of the Wnt pathway and of T together with axis truncationswas also observed in Hox13 over-expressing transgenic mice (Young et al., 2009). Our data suggest that thegradient of T activity is established by the graded regulation of Wnt signaling byposterior Hox genes, (Figure11) thus providing a possible explanation for these complex phenotypes. At thecellular level, it argues that the Hox-dependent regulation of T levelsin the epiblast is critical to control the balance between cell ingression andmaintenance of a self-renewing paraxial mesoderm progenitor pool in theepiblast/tail-bud. Cell ingression requires an EMT that involves destabilization of thebasal microtubules of epiblast cells followed by basal membrane breakdown (Nakaya et al., 2008). Inhibiting Rhoa activity canrescue the ingression delay caused by Hoxa13 overexpression, suggestingthat posterior Hox genes can control cell flux to the PM by acting onbasal microtubule stabilization in epiblast cells. As T is also able to rescueHoxa13 phenotype on elongation, it could act upstream of thisprocess and the details of such a molecular pathway remain to be investigated.10.7554/eLife.04379.027Figure 11.Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.


Hox genes control vertebrate body elongation by collinear Wnt repression.

Denans N, Iimura T, Pourquié O - Elife (2015)

Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.Model representing the 3 phases (I, II, and III) of Hox actionin PSM precursors in the epiblast/tail-bud during body axis elongation.Anterior Hox genes (paralogs 1–9) are expressed duringphase I. They control cell ingression in a Pbx1-dependentmanner leading to the collinear positioning of Hox genesexpression domains in the anterior region of the embryo. NoHox genes are activated during phase II, allowing fastelongation of the embryonic axis. During phase III, posteriorHox genes (paralogs 9–13) are collinearly activatedin PSM precursors. Our data suggest that collinear activation of posteriorHox genes leads to repression of Wnt signaling and itstarget T/Brachyury, which progressively increases in strength.This results in a progressive arrest of cell ingression in the PSM, leading toa decrease in axis elongation rate. Since the velocity of somite formation isroughly constant, PSM size starts to decrease when elongation velocity becomesslower than that of somite formation. During this latter phase the control ofcell ingression by posterior Hox genes appears to beindependent of Pbx1.DOI:http://dx.doi.org/10.7554/eLife.04379.027
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Related In: Results  -  Collection

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fig11: Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.Model representing the 3 phases (I, II, and III) of Hox actionin PSM precursors in the epiblast/tail-bud during body axis elongation.Anterior Hox genes (paralogs 1–9) are expressed duringphase I. They control cell ingression in a Pbx1-dependentmanner leading to the collinear positioning of Hox genesexpression domains in the anterior region of the embryo. NoHox genes are activated during phase II, allowing fastelongation of the embryonic axis. During phase III, posteriorHox genes (paralogs 9–13) are collinearly activatedin PSM precursors. Our data suggest that collinear activation of posteriorHox genes leads to repression of Wnt signaling and itstarget T/Brachyury, which progressively increases in strength.This results in a progressive arrest of cell ingression in the PSM, leading toa decrease in axis elongation rate. Since the velocity of somite formation isroughly constant, PSM size starts to decrease when elongation velocity becomesslower than that of somite formation. During this latter phase the control ofcell ingression by posterior Hox genes appears to beindependent of Pbx1.DOI:http://dx.doi.org/10.7554/eLife.04379.027
Mentions: Genetic studies on mouse T mutants have shown that graded T activity is required forbody axis formation (Stott et al., 1993; Wilson and Beddington, 1997). Embryos withprogressively lower quantities of T exhibit more severe axis truncations (Stott et al., 1993). Similar graded truncationsare also observed for Wnt3a allelic series (Galceran et al., 1999), indicating that precise quantitativeregulation of this pathway is required for completion of body axis elongation.Repression of the Wnt pathway and of T together with axis truncationswas also observed in Hox13 over-expressing transgenic mice (Young et al., 2009). Our data suggest that thegradient of T activity is established by the graded regulation of Wnt signaling byposterior Hox genes, (Figure11) thus providing a possible explanation for these complex phenotypes. At thecellular level, it argues that the Hox-dependent regulation of T levelsin the epiblast is critical to control the balance between cell ingression andmaintenance of a self-renewing paraxial mesoderm progenitor pool in theepiblast/tail-bud. Cell ingression requires an EMT that involves destabilization of thebasal microtubules of epiblast cells followed by basal membrane breakdown (Nakaya et al., 2008). Inhibiting Rhoa activity canrescue the ingression delay caused by Hoxa13 overexpression, suggestingthat posterior Hox genes can control cell flux to the PM by acting onbasal microtubule stabilization in epiblast cells. As T is also able to rescueHoxa13 phenotype on elongation, it could act upstream of thisprocess and the details of such a molecular pathway remain to be investigated.10.7554/eLife.04379.027Figure 11.Model representing the 3 phases (I, II, and III) of Hoxaction in PM precursors in the epiblast/tail-bud during axiselongation.

Bottom Line: Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength.This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process.Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size.

View Article: PubMed Central - PubMed

Affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, University of Strasbourg, Illkirch, France.

ABSTRACT
In vertebrates, the total number of vertebrae is precisely defined. Vertebrae derive from embryonic somites that are continuously produced posteriorly from the presomitic mesoderm (PSM) during body formation. We show that in the chicken embryo, activation of posterior Hox genes (paralogs 9-13) in the tail-bud correlates with the slowing down of axis elongation. Our data indicate that a subset of progressively more posterior Hox genes, which are collinearly activated in vertebral precursors, repress Wnt activity with increasing strength. This leads to a graded repression of the Brachyury/T transcription factor, reducing mesoderm ingression and slowing down the elongation process. Due to the continuation of somite formation, this mechanism leads to the progressive reduction of PSM size. This ultimately brings the retinoic acid (RA)-producing segmented region in close vicinity to the tail bud, potentially accounting for the termination of segmentation and axis elongation.

Show MeSH
Related in: MedlinePlus