20 januari 2015

Cdx2 is essential for embryonic axial growth and identity of adult intestinal stem cells

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During embryo development and in adult, stem cells regulate generation and homeostasis of all the body tissues. The research described in this thesis has been focused in investigating the molecular role played by specific transcription factors in controlling stem cell fate and functions both in embryos and adult mice. The research has been performed in the group of Jacqueline Deschamps.

In the mouse embryo, progenitor cells, located posteriorly lay down descendants that generate primordia of the trunk and tail tissues. Along the primitive streak and in the tailbud, a pool of these progenitor cells, with stem cell-like properties, contributes to the formation of neuroectoderm and mesoderm tissues during the elongation of the embryo body. These cells, called long-term Neuro-Mesodermal axial progenitors, together with other cells present in the same region, from caudal lateral epiblast, form the embryonic posterior growth zone.

The three mouse Cdx genes encode transcription factors involved in elongation and patterning of the embryonic axial structures. They are all expressed in the posterior growth zone. To reveal the extent of the role played by these genes in regulating axial elongation, triple Cdxnull mutant embryos have been generated and characterized. These mutants lose activity of their posterior growth zone and fail to generate axial tissues posterior to occipital primordia structures. The results show that Cdx genes are crucial for trunk and posterior tissue generation by regulating downstream signalings, such as Fgf and Wnt, in the growth zone.

Cdx2 is, among the three Cdx genes, the main contributor to the axial elongation. Another transcription factor, T Brachyury,is expressed in the growth zone and is crucial for posterior axial extension. Cdx2 and T Brachyury support this process by positively regulating Fgf and Wnt signalings. However, whether they interact in another way it is still unclear. To better investigate the role played by Cdx2 andT Brachyury during axial elongation, Cdx2null/T Brachyurynull mutant embryos have been generated. Their simultaneous loss of function disrupts axial elongation much more severely than each single mutation. The results suggest that Cdx2 and T Brachyurycooperate in regulating parallel pathways during mouse development and that these pathways would interact during the generation of the trunk and tail.

The epithelia of the gastric pylorus and of the small intestine carry functional units called stomach glands and intestinal crypts/villi, respectively. They harbor actively cycling Lgr5-expressing stem cells that are responsible for the renewal of both epithelia throughout life. Isolated Lgr5-positive intestinal and stomach stem cells can generate 3D structures in vitro, made of epithelium that recapitulates the epithelium of their organ of origin. Taking advantage of this organoid culture system, it has been shown that Cdx2 is absolutely required for maintaining the identity of the adult intestinal stem cells. Intestinal stem cells mutant for Cdx2 gene give rise to organoids that resemble stomach organoids and express markers of the gastric pylorus. The data indicate that Cdx2 is cell autonomously required in the adult intestinal stem cells for keeping their identity and for supporting the continuous regeneration of the intestinal epithelium.