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Research objectives

Genetics of morphogenesis during axial elongation in the mouse embryo

Genetic basis of antero-posterior patterning in the mouse
Antero-posterior (A-P) regionalisation of the mammalian embryo begins before gastrulation is initiated. Genetic events occurring later in the caudal aspect of the embryo lead to posterior extension of the main axis and to patterning of the emerging structures.Hox and Cdx genes are key players in the acquisition by the nascent tissues, of correct positional identity and morphology. The importance of Hox and Cdx genes in body patterning is attested by their extremely strong conservation among phyla, and by mutant phenotypes in several species.

Hox genes
Hox genes encode a family of transcriptional regulatory proteins with a highly conserved role in axial patterning in all bilaterians. The chromosomal organisation of these genes in clusters is intimately linked to regulatory constraints, which couple gene expression to the progression of embryogenesis in vertebrates. Expression of the Hox genes begins during gastrulation, at the posterior end of the primitive streak. 3'Hox genes start being expressed earlier than their 5' counterparts.
Some at least of the Hox genes remain expressed in adult tissues, for example in the developing nervous system where they play a patterning role.

Cdx genes
Cdx genes, homologs of Drosophila Caudal, belong to ParaHox genes. They are relatives of the Hox genes, in that both share common ancestors, the Proto-Hox genes. Cdx genes, like Hox genes, contribute to the specification of axial identity of tissues such as the prevertebrae and the posterior gut. Two of the three Cdx genes remain differentially expressed in the adult gut endoderm and we recently demonstrated that Cdx2 is essential to maintain the idendity and fate of the adult intestinal stem cells.. In the absence of Cdx2, these stem cells are transformed into gastric pyloric stem cells.

Cdx and Hox genes and body axis elongation.
We discovered an unanticipated involvement of Hox genes, like their Cdx counterparts in the posterior extension of the embryonic axis in the three germ layers in the mouse (Young et al., 2009). We also elucidated part of the mechanism underlying this control: trunk Hox genes and Cdx genes stimulate axial growth by maintening active Wnt signaling and clearing retinoic acid in the embryonic stem zone. On the other hand, postermost Hox genes (Hox13 members) arrest axial extension after the trunk-tail transition by antagonizing more anterior Hox genes. Thus Hox genes differentially orchestrate posterior expansion of posterior embryonic tissues during axial morphogenesis, as an integral part of their function in specifying head-to-tail identity.

Conserved mechanism for posterior axial growth
Cdx and Wnt genes were proven to be required for body axis extension in many species from vertebrates to short germ band insects and in crustaceans, indicating the conservation of the genetic mechanism of body axis elongation throughout bilaterians. It is not know yet whether Hox genes also modulate axial growth in these organisms. In vertebrates in any case, the importance of a well timed and well balanced expression of Hox and Cdx genes for axial growth, and their action via Wnt signaling suggests that these parameters of timing and dosage might well be substrates for evolution towards elongated body plans.

Current research
Our current research focuses on the early transcriptional regulation of Hox and Cdx genes, and on the mechanism of action of   these genes in axial extension and patterning in the mouse embryo. We also aim at unravelling the relationship between these genes and other transcription factors and signaling pathways known to be involved in posterior tissue generation. We want to understand how these genetic networks affect the axial progenitors that are known to reside in the posterior growth zone of the developing embryo. We work on the characterization of the axial stem zone in mutants versus wild type embryos, and on the mapping of interactions between the key transcription factors and their genomic targets.


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Sequential activation of Hox gene expression

Hox genes are sequentially activated during embryogenesis (temporal colinearity)

 

 

Hox and Cdx expression in the precirsor domain of trunk and tail

Cdx and Hox genes are expressed in the primitive streak at E7.5, the progenitor region for trunk and tail

 

 

 

image description

Cdx compound mutant embryos are posteriorly truncated (note reduced tailbud size in the E8.5 mutant)

 

 

 

Interactions between players in axial extension

Expression of trunk Hox and Cdx genes (green), activity of the canonical Wnt pathway (blue) and RA clearance (orange) during axial extension. Hox13 genes are expressed (red) at and after the trunk-tail transition (brown double arrow)
(Young et al., Dev Cell 2009)