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Gene Review

Cdx2  -  caudal type homeobox 2

Mus musculus

Synonyms: Caudal-type homeobox protein 2, Cdx-2, Homeobox protein CDX-2
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Disease relevance of Cdx2


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


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


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


Analytical, diagnostic and therapeutic context of Cdx2


  1. Homeosis and intestinal tumours in Cdx2 mutant mice. Chawengsaksophak, K., James, R., Hammond, V.E., Köntgen, F., Beck, F. Nature (1997) [Pubmed]
  2. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Hinoi, T., Gesina, G., Akyol, A., Kuick, R., Hanash, S., Giordano, T.J., Gruber, S.B., Fearon, E.R. Gastroenterology (2005) [Pubmed]
  3. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Silberg, D.G., Sullivan, J., Kang, E., Swain, G.P., Moffett, J., Sund, N.J., Sackett, S.D., Kaestner, K.H. Gastroenterology (2002) [Pubmed]
  4. Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Tamai, Y., Nakajima, R., Ishikawa, T., Takaku, K., Seldin, M.F., Taketo, M.M. Cancer Res. (1999) [Pubmed]
  5. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Niwa, H., Toyooka, Y., Shimosato, D., Strumpf, D., Takahashi, K., Yagi, R., Rossant, J. Cell (2005) [Pubmed]
  6. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice. Aoki, K., Tamai, Y., Horiike, S., Oshima, M., Taketo, M.M. Nat. Genet. (2003) [Pubmed]
  7. Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. Mutoh, H., Satoh, K., Kita, H., Sakamoto, H., Hayakawa, H., Yamamoto, H., Isoda, N., Tamada, K., Ido, K., Sugano, K. Int. J. Dev. Biol. (2005) [Pubmed]
  8. Cdx1 and cdx2 expression during intestinal development. Silberg, D.G., Swain, G.P., Suh, E.R., Traber, P.G. Gastroenterology (2000) [Pubmed]
  9. Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal cell differentiation. Lorentz, O., Duluc, I., Arcangelis, A.D., Simon-Assmann, P., Kedinger, M., Freund, J.N. J. Cell Biol. (1997) [Pubmed]
  10. Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene. Boudreau, F., Rings, E.H., van Wering, H.M., Kim, R.K., Swain, G.P., Krasinski, S.D., Moffett, J., Grand, R.J., Suh, E.R., Traber, P.G. J. Biol. Chem. (2002) [Pubmed]
  11. Pdx1-related homeodomain transcription factors are distinctly expressed in mouse adult pancreatic islets. Rosanas-Urgell, A., Marfany, G., Garcia-Fernàndez, J. Mol. Cell. Endocrinol. (2005) [Pubmed]
  12. Comparison of intestinal phospholipase A/lysophospholipase and sucrase-isomaltase genes suggest a common structure for enterocyte-specific promoters. Taylor, J.K., Boll, W., Levy, T., Suh, E., Siang, S., Mantei, N., Traber, P.G. DNA Cell Biol. (1997) [Pubmed]
  13. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Strumpf, D., Mao, C.A., Yamanaka, Y., Ralston, A., Chawengsaksophak, K., Beck, F., Rossant, J. Development (2005) [Pubmed]
  14. The Cdx4 mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice. van Nes, J., de Graaff, W., Lebrin, F., Gerhard, M., Beck, F., Deschamps, J. Development (2006) [Pubmed]
  15. Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation. van den Akker, E., Forlani, S., Chawengsaksophak, K., de Graaff, W., Beck, F., Meyer, B.I., Deschamps, J. Development (2002) [Pubmed]
  16. Phosphorylation of the serine 60 residue within the Cdx2 activation domain mediates its transactivation capacity. Rings, E.H., Boudreau, F., Taylor, J.K., Moffett, J., Suh, E.R., Traber, P.G. Gastroenterology (2001) [Pubmed]
  17. The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Bonhomme, C., Duluc, I., Martin, E., Chawengsaksophak, K., Chenard, M.P., Kedinger, M., Beck, F., Freund, J.N., Domon-Dell, C. Gut (2003) [Pubmed]
  18. Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: an active role for the tumor environment in malignant tumor progression. Brabletz, T., Spaderna, S., Kolb, J., Hlubek, F., Faller, G., Bruns, C.J., Jung, A., Nentwich, J., Duluc, I., Domon-Dell, C., Kirchner, T., Freund, J.N. Cancer Res. (2004) [Pubmed]
  19. The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1alpha in mice. de Koning, B.A., Lindenbergh-Kortleve, D.J., Pieters, R., Rings, E.H., Büller, H.A., Renes, I.B., Einerhand, A.W. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  20. Misexpression of the pancreatic homeodomain protein IDX-1 by the Hoxa-4 promoter associated with agenesis of the cecum. Heller, R.S., Stoffers, D.A., Hussain, M.A., Miller, C.P., Habener, J.F. Gastroenterology (1998) [Pubmed]
  21. Pax6 and Cdx2/3 form a functional complex on the rat glucagon gene promoter G1-element. Andersen, F.G., Heller, R.S., Petersen, H.V., Jensen, J., Madsen, O.D., Serup, P. FEBS Lett. (1999) [Pubmed]
  22. Clusterin gene transcription is activated by caudal-related homeobox genes in intestinal epithelium. Suh, E., Wang, Z., Swain, G.P., Tenniswood, M., Traber, P.G. Am. J. Physiol. Gastrointest. Liver Physiol. (2001) [Pubmed]
  23. Regulation of RELM/FIZZ isoform expression by Cdx2 in response to innate and adaptive immune stimulation in the intestine. Wang, M.L., Shin, M.E., Knight, P.A., Artis, D., Silberg, D.G., Suh, E., Wu, G.D. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  24. Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog. Hough, S.R., Clements, I., Welch, P.J., Wiederholt, K.A. Stem Cells (2006) [Pubmed]
  25. Homeobox gene expression in the intestinal epithelium of adult mice. James, R., Kazenwadel, J. J. Biol. Chem. (1991) [Pubmed]
  26. Changing intestinal connective tissue interactions alters homeobox gene expression in epithelial cells. Duluc, I., Lorentz, O., Fritsch, C., Leberquier, C., Kedinger, M., Freund, J.N. J. Cell. Sci. (1997) [Pubmed]
  27. Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation. Gross, I., Lhermitte, B., Domon-Dell, C., Duluc, I., Martin, E., Gaiddon, C., Kedinger, M., Freund, J.N. Oncogene (2005) [Pubmed]
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