Disease relevance of Cdx2

• Within the first three months of life, 90% of Cdx2 heterozygotes develop multiple intestinal adenomatous polyps, particularly in the proximal colon [1].
• Mice heterozygous for Cdx2 inactivation develop colonic polyps with epithelial cells showing gastric or squamous differentiation [2].
• CONCLUSIONS: Gastric expression of Cdx2 alone was sufficient to induce intestinal metaplasia in mice [3].
• Moreover, as gastric cancer in humans is often preceded by intestinal metaplasia, the phenotype described here strongly suggests involvement of Cdx2 in the initiation of the process leading to intestinal neoplasia of the gastric mucosa [3].
• Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice [4].

High impact information on Cdx2

• In preimplantation embryos, Cdx2 is initially coexpressed with Oct3/4 and they form a complex for the reciprocal repression of their target genes in ES cells [5].
• We show here that this event can be mimicked by overexpression of Caudal-related homeobox 2 (Cdx2), which is sufficient to generate proper trophoblast stem (TS) cells [5].
• We obtained similar results in the colonic mucosa of Apc+/Delta716) Cdx2+/- compound mutant mice [6].
• Heterozygous Cdx2 mice develop one or two benign hamartomas in the proximal colon, whereas heterozygous Apc(Delta716) mice develop numerous adenomatous polyps, mostly in the small intestine [6].
• Here we show that the colonic polyp number is about six times higher in Apc+/Delta716 Cdx2+/- compound mutant mice [6].

Chemical compound and disease context of Cdx2

• Glucose and amino acids were absorbed from Cdx2 transgenic mouse stomach with intestinal metaplasia [7].

Biological context of Cdx2

• BACKGROUND & AIMS: The intestine-specific transcription factors Cdx1 and Cdx2 are candidate genes for directing intestinal development, differentiation, and maintenance of the intestinal phenotype [8].
• In the present study, we demonstrate that the differentiating effect of laminin-1 coatings on Caco2-TC7 cells is accompanied by an upregulation of Cdx2 [9].
• We wanted to study whether HNF-1 alpha, GATA-4, and Cdx2 can cooperate in the regulation of SI gene expression [10].
• To our knowledge, this is the first report that locates ParaHox genes other than Pdx1 and Cdx2/3 in a place as to be involved in the pancreatic transcriptional regulatory networks, potentially regulating glucagon-insulin homeostasis [11].
• The IPAL-FP1 element was shown to be a monomer binding site for Cdx1 and Cdx2, intestine-specific homeobox proteins [12].

Anatomical context of Cdx2

• In contrast to the surrounding intestinal epithelium, the neoplastic cells do not express Cdx2 from the remaining allele [1].
• We found a positive correlation between the level of Cdx2 expression, that of endogenous laminin-alpha1 chain mRNA and that of sucrase-isomaltase expression in these cell lines [9].
• Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst [13].
• In a subset of Cdx2/Cdx4 compound mutants, the fully grown allantois failed to fuse with the chorion [14].
• Cdx2-null embryos die before gastrulation, and Cdx2 heterozygotes display anterior transformations of lower cervical and thoracic vertebrae [15].

Associations of Cdx2 with chemical compounds

• To study a potential phosphorylation site, polyclonal antibodies were generated: CNL was raised against amino acids 54-66 of Cdx2 and P-Cdx2-S60 against the same epitope in which serine 60 was phosphorylated [16].
• However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage [17].
• Cell culture experiments show that collagen type I, through beta(1) integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation [18].
• HNF-1alpha, Cdx2 and GATA-4 are critical transcription factors in epithelial differentiation, and in combination they act as promoting factors of the sucrase-isomaltase (SI) gene, an enterocyte-specific differentiation marker which is distinctly downregulated after MTX treatment [19].
• The objective of this study was to investigate the gene expression of the small intestinal transcription factors HNF-1alpha, Cdx2, GATA-4 in an experimental model of methotrexate (MTX)-induced intestinal damage, and to correlate these alterations with histological damage, epithelial proliferation and differentiation [19].

Physical interactions of Cdx2

• Further, IDX-1 binds to the gut-specific homeodomain protein Cdx-2 and inhibits transactivation of the sucrase-isomaltase promoter by Cdx-2 [20].
• Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1-element [21].

Regulatory relationships of Cdx2

• Loss of Cdx2 results in failure to downregulate Oct4 and Nanog in outer cells of the blastocyst and subsequent death of those cells [13].
• Using cDNA differential display, we identified clusterin as a prominently induced gene in a Cdx2-regulated cellular model of intestinal differentiation [22].
• Additionally, Pax6 enhanced Cdx2/3 mediated activation of a glucagon reporter in heterologous cells [21].
• This was confirmed in vivo using transgenic mice, where ectopic gastric and hepatic expression of Cdx2 induces expression of RELM beta, but not RELM alpha or RELM gamma, exclusively in the stomach [23].

Other interactions of Cdx2

• The relative expression of Cdx1 to Cdx2 protein may be important in the anterior to posterior patterning of the intestinal epithelium and in defining patterns of proliferation and differentiation along the crypt-villus axis [8].
• However, Eomes mutant blastocysts implant, and Cdx2 and Oct4 expression are correctly restricted to the ICM TE [13].
• HNF-1 alpha, GATA-4, and Cdx2 interact in vitro and in vivo [10].
• Reduction in OCT4 expression correlated with induction of trophectoderm genes Cdx2, Hand1, and PL-1, with formation of cells with trophoblast giant cell phenotype after 6 days [24].
• RESULTS: Histologic examination of the gastric mucosa of the Foxa3/Cdx2 mice revealed the presence of alcian blue-positive intestinal-type goblet cells, a hallmark of intestinal metaplasia [3].

Analytical, diagnostic and therapeutic context of Cdx2

• METHODS: Embryonic and postnatal mouse tissues were analyzed by immunohistochemistry to determine protein expression of Cdx1 and Cdx2 in the developing intestinal tract [8].
• METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane [17].
• Southern blot experiments show that Cdx-2 is present in a single copy in the mouse genome [25].
• Using a xenograft model of fetal intestinal anlagen implanted under the skin of nude mice, we have investigated whether the expression of five homeobox genes (HoxA-4, HoxA-9, HoxC-8, Cdx-1 and Cdx-2) is modified when intestinal epithelium undergoes normal development or displays heterodifferentiation in association with heterotopic mesenchyme [26].
• Using site-specific mutagenesis, we identified serine 281 as a new key residue for Cdx2 phosphorylation [27].

References