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

Salvatore Simmini

Research output: PhD ThesisPhD thesis

Abstract

During mouse development, progenitor cells, allocated along the primitive streak and in the tailbud, lay down descendants that contribute to the generation of all primordia of the trunk and tail tissues of the embryo. Evidence suggested that a pool of these progenitor cells, with stem cell-like potential, contribute to the neuroectoderm and mesoderm during axial elongation of the trunk and tail. These so called, long-term bipotent Neuro-Mesodermal axial progenitors, together with the caudal lateral epiblast in the primitive streak area, form the embryonic posterior growth zone. In this region Cdx genes encode transcription factors involved in elongation and patterning of the axial structures. In order to reveal the extent of the role played by these genes in the laying down of the mouse embryonic trunk and tail tissues we generated and characterized the triple Cdxnull mutants. These mutants affect the activity of the axial progenitors in the posterior growth zone and fail to generate any axial tissue posterior to occipital primordia. Our data indicate that Cdx genes are crucial for trunk generation and for regulating downstream Fgf and Wnt signaling in this process. Generation of Cdx compound mutants and comparison of their phenotypes made clear that Cdx2 is, among the three Cdx genes, the most active in axial elongation. Another transcription factor, T Brachyury, is expressed in the growth zone and is crucial for the posterior axial extension. Cdx2 and T Brachyury support this process by positively regulating the Fgf and Wnt pathways. However, whether they interact in another way it is still unclear. To better investigate the role played by Cdx2 and T Brachyury during axial elongation we generated Cdx2null/T Brachyurynull mutant embryos. We show that the simultaneous loss of function of these two genes disrupts axial elongation much more severely than each single mutation. We discuss whether Cdx2 and T Brachyury cooperate in regulating parallel pathways during mouse development and how 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 villi/crypts, 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 epithelial structures in vitro that recapitulate the epithelium of their organ of origin. Taking advantage of this organoid culture system, we show that Cdx2 expression is absolutely required for maintaining the identity of the adult intestinal stem cells. Cdx2null intestinal stem cells show a stomach instead of an intestinal signature and give rise to organoids that resemble stomach organoids and express markers of the gastric pylorus. Our data indicate that Cdx2 is cell autonomously required in the adult intestinal stem cells to keep them self-renewing and to maintain their intestinal differentiation program. We provide evidence of the plasticity of adult stem cells in which the intestinal commitment can be converted into a gastric one upon inactivation of the single transcription factor Cdx2.
Original languageEnglish
Awarding Institution
Supervisors/Advisors
  • Clevers, Hans, Promotor
  • Deschamps, Jacqueline, Co-promotor
Award date20 Jan 2015
Publisher
Publication statusPublished - 20 Jan 2015

Keywords

  • Mouse Embryo
  • Axial elongation
  • Transcription factors
  • Stem Cells
  • Intestines
  • Stomach
  • Organoids
  • Cell fate
  • Reprogramming
  • Progenitors

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