CDX2

Homeobox protein CDX-2 is a protein that in humans is encoded by the CDX2 gene. The CDX2 protein is a homeobox transcription factor expressed in the nuclei of intestinal epithelial cells,[5][6] playing an essential role in the development and function of the digestive system. CDX2 part of the ParaHox gene cluster, a group of three highly conserved developmental genes present in most vertebrate species.[7] Together with CDX1 and CDX4, CDX2 is one of three caudal-related genes in the human genome.

CDX2
Identifiers
AliasesCDX2, CDX-3, CDX2/AS, CDX3, caudal type homeobox 2, Cdx2
External IDsOMIM: 600297 MGI: 88361 HomoloGene: 968 GeneCards: CDX2
Orthologs
SpeciesHumanMouse
Entrez

1045

12591

Ensembl

ENSG00000165556

ENSMUSG00000029646

UniProt

Q99626

P43241

RefSeq (mRNA)

NM_001265
NM_001354700

NM_007673

RefSeq (protein)

NP_001256
NP_001341629

NP_031699

Location (UCSC)Chr 13: 27.96 – 27.97 MbChr 5: 147.24 – 147.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

In common with the two other Cdx genes, CDX2 regulates several essential processes in the development and function of the lower gastrointestinal tract (from the duodenum to the anus) in vertebrates. In vertebrate embryonic development, CDX2 becomes active in endodermal cells that are posterior to the developing stomach.[6] These cells eventually form the intestinal epithelium. The activity of CDX2 at this stage is essential for the correct formation of the intestine and the anus.[8][9] CDX2 is also required for the development of the placenta.[9]

Later in development, CDX2 is expressed in intestinal epithelial stem cells, which are cells that continuously differentiate into the cells that form the intestinal lining. This differentiation is dependent on CDX2,[10][11] as illustrated by experiments where the expression of this gene was knocked-out or overexpressed in mice. Heterozygous CDX2 knock-outs have intestinal lesions caused by the differentiation of intestinal cells into gastric epithelium; this can be considered a form of homeotic transformation.[12] Conversely, the over-expression of CDX2 leads to the formation of intestinal epithelium in the stomach.[13]

In addition to roles in endoderm, CDX2 is also expressed in very early stages of mouse and human embryonic development, specifically marking the trophectoderm lineage of cells in the blastocyst of mouse and human. Trophectoderm cells contribute to the placenta.[9]

Pathology

Ectopic expression of CDX2 was reported in more than 85% of the human patients with acute myeloid leukemia (AML). Ectopic expression of Cdx2 in murine bone marrow induced AML in mice and upregulate Hox genes in bone marrow progenitors.[14][15] CDX2 is also implicated in the pathogenesis of Barrett's esophagus where it has been shown that components from gastroesophageal reflux such as bile acids are able to induce the expression of an intestinal differentiation program through up-regulation of NF-κB and CDX2.[16]

Biomarker for intestinal cancer

CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal.[17]

Possible use in stem cell research

This gene (or, more specifically, the equivalent gene in humans) has come up in the proposal by the President's Council on Bioethics, as a solution to the stem cell controversy.[18] According to one of the plans put forth, by deactivating the gene, it would not be possible for a properly organized embryo to form, thus providing stem cells without requiring the destruction of an embryo.[19] Other genes that have been proposed for this purpose include Hnf4, which is required for gastrulation.[18][20]

Interactions

CDX2 has been shown to interact with EP300,[21] and PAX6.[21]

References
  1. GRCh38: Ensembl release 89: ENSG00000165556 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029646 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. German MS, Wang J, Fernald AA, Espinosa R, Le Beau MM, Bell GI (Nov 1994). "Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13". Genomics. 24 (2): 403–4. doi:10.1006/geno.1994.1639. PMID 7698771.
  6. Beck, F.; Erler, T.; Russell, A.; James, R. (1995). "Expression of Cdx-2 in the mouse embryo and placenta: Possible role in patterning of the extra-embryonic membranes". Developmental Dynamics. 204 (3): 219–227. doi:10.1002/aja.1002040302. PMID 8573715. S2CID 19576530.
  7. Brooke, Nina M.; Garcia-Fernàndez, Jordi; Holland, Peter W. H. (1998). "The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster". Nature. 392 (6679): 920–922. doi:10.1038/31933. ISSN 0028-0836. PMID 9582071. S2CID 4398740.
  8. Chawengsaksophak, K.; James, R.; Hammond, V. E.; Köntgen, F.; Beck, F. (1997). "Homeosis and intestinal tumours in Cdx2 mutant mice". Nature. 386 (6620): 84–87. Bibcode:1997Natur.386...84C. doi:10.1038/386084a0. ISSN 1476-4687. PMID 9052785. S2CID 4252265.
  9. Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F (May 2004). "Cdx2 is essential for axial elongation in mouse development". Proceedings of the National Academy of Sciences of the United States of America. 101 (20): 7641–5. Bibcode:2004PNAS..101.7641C. doi:10.1073/pnas.0401654101. PMC 419659. PMID 15136723.
  10. Simmini, Salvatore; Bialecka, Monika; Huch, Meritxell; Kester, Lennart; van de Wetering, Marc; Sato, Toshiro; Beck, Felix; van Oudenaarden, Alexander; Clevers, Hans; Deschamps, Jacqueline (2014-12-11). "Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2". Nature Communications. 5 (1): 5728. doi:10.1038/ncomms6728. ISSN 2041-1723. PMC 4284662. PMID 25500896.
  11. Stringer, Emma J.; Duluc, Isabelle; Saandi, Thoueiba; Davidson, Irwin; Bialecka, Monika; Sato, Toshiro; Barker, Nick; Clevers, Hans; Pritchard, Catrin A.; Winton, Doug J.; Wright, Nicholas A. (2012-02-01). "Cdx2 determines the fate of postnatal intestinal endoderm". Development. 139 (3): 465–474. doi:10.1242/dev.070722. ISSN 0950-1991. PMC 3252350. PMID 22190642.
  12. Beck, Felix; Chawengsaksophak, Kallayanee; Waring, Paul; Playford, Raymond J.; Furness, John B. (1999-06-22). "Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice". Proceedings of the National Academy of Sciences. 96 (13): 7318–7323. doi:10.1073/pnas.96.13.7318. ISSN 0027-8424. PMC 22083. PMID 10377412.
  13. Mutoh, Hiroyuki; Hakamata, Yoji; Sato, Kiichi; Eda, Akashi; Yanaka, Ichiro; Honda, Sayaka; Osawa, Hiroyuki; Kaneko, Yoshinari; Sugano, Kentaro (2002). "Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice". Biochemical and Biophysical Research Communications. 294 (2): 470–479. doi:10.1016/s0006-291x(02)00480-1. ISSN 0006-291X. PMID 12051735.
  14. Rawat VP, Cusan M, Deshpande A, Hiddemann W, Quintanilla-Martinez L, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C (Jan 2004). "Ectopic expression of the homeobox gene CDX2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia". Proceedings of the National Academy of Sciences of the United States of America. 101 (3): 817–22. Bibcode:2004PNAS..101..817R. doi:10.1073/pnas.0305555101. PMC 321764. PMID 14718672.
  15. Scholl C, Bansal D, Döhner K, Eiwen K, Huntly BJ, Lee BH, Rücker FG, Schlenk RF, Bullinger L, Döhner H, Gilliland DG, Fröhling S (Apr 2007). "The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis". The Journal of Clinical Investigation. 117 (4): 1037–48. doi:10.1172/JCI30182. PMC 1810574. PMID 17347684.
  16. Debruyne PR, Witek M, Gong L, Birbe R, Chervoneva I, Jin T, Domon-Cell C, Palazzo JP, Freund JN, Li P, Pitari GM, Schulz S, Waldman SA (Apr 2006). "Bile acids induce ectopic expression of intestinal guanylyl cyclase C Through nuclear factor-kappaB and Cdx2 in human esophageal cells". Gastroenterology. 130 (4): 1191–206. doi:10.1053/j.gastro.2005.12.032. PMID 16618413.
  17. Liu Q, Teh M, Ito K, Shah N, Ito Y, Yeoh KG (Dec 2007). "CDX2 expression is progressively decreased in human gastric intestinal metaplasia, dysplasia and cancer". Modern Pathology. 20 (12): 1286–97. doi:10.1038/modpathol.3800968. PMID 17906616.
  18. Hurlbut WB (2004). "Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells". The President's Council on Bioethics. The White House of the United States of America. Archived from the original on May 17, 2008. Retrieved 2008-07-16.
  19. Saletan, William (2004-12-06). "The creepy solution to the stem-cell debate". Slate. Archived from the original on February 14, 2007. Retrieved 2008-07-16.
  20. Hurlbut WB (2007). "Ethics and embryonic stem cell research: altered nuclear transfer as a way forward". BioDrugs. 21 (2): 79–83. doi:10.2165/00063030-200721020-00002. PMID 17402791. S2CID 26102470.
  21. Hussain MA, Habener JF (Oct 1999). "Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator". The Journal of Biological Chemistry. 274 (41): 28950–7. doi:10.1074/jbc.274.41.28950. PMID 10506141.

Further reading
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