Alternative titles; symbols
HGNC Approved Gene Symbol: CDX2
Cytogenetic location: 13q12.2 Genomic coordinates (GRCh38): 13:27,960,918-27,969,315 (from NCBI)
The level and beta-cell specificity of insulin gene expression are regulated by a set of nuclear proteins that bind to specific sequences within the promoter of the insulin gene (INS; 176730) and interact with RNA polymerase to activate or repress transcription. The proteins LMX1 (600298) and CDX3 are homeodomain proteins that bind an A/T-rich sequence in the insulin promoter and stimulate its transcription (German et al., 1994).
Drummond et al. (1997) cloned the CDX2 (CDX3) cDNA from a human jejunal cDNA library and reported its nucleotide and protein sequences.
Inactivation of Cdx2 in the mouse leads to preimplantation embryonic lethality. Rescue of the implantation defect by tetraploid fusion established that Cdx2 is necessary for trophoblastic development, vasculogenesis in the yolk sac mesoderm, allantoic growth, and chorioallantoic fusion. Chawengsaksophak et al. (2004) found that 'rescued' Cdx2 mutants die at late gastrulation stages because of failure of placental development. Cdx2 is also needed for the completion of the normal process of gastrulation and tail bud elongation. The Cdx2 mutation, like mutations impairing Wnt (see 164820) and Fgf (see 131220) signaling, causes posterior truncations and disturbs axial patterning of the embryonic structures, indicated by changes in the Hox expression domains. The gene appears to be important in the integration of the pathways controlling embryonic axial elongation and anterior/posterior patterning.
Altered nuclear transfer has been proposed as a variation of nuclear transfer that would create abnormal nuclear transfer blastocysts that are inherently unable to implant into the uterus but would be capable of generating customized ES cells. To assess the experimental validity of this concept, Meissner and Jaenisch (2006) used nuclear transfer to derive mouse blastocysts from donor fibroblasts that carried a short hairpin RNA construct targeting Cdx2. Cloned blastocysts were morphologically abnormal, lacked functional trophoblast, and failed to implant into the uterus. However, they efficiently generated pluripotent embryonic stem cells when explanted into culture.
Using quantitative PCR, Gregory et al. (2006) found that levels of CDX2 and UGT2B7 (600068) mRNA were coordinately increased in differentiated human CACO2 cells, a colon-derived cell line, compared with nondifferentiated cells. Activation of the UGT2B7 proximal promoter required CDX2 binding to 2 adjacent sites. CDX2 cooperatively activated the UGT2B7 promoter in conjunction with HNF1-alpha (TCF1; 142410), a mechanism previously observed to regulate other intestine-specific genes.
Grainger et al. (2013) noted that CDX1 (600746) and LEF1 (153245) act through the CDX1 proximal promoter to regulate CDX1 expression, forming an autoregulatory loop. Using transfected P19 mouse embryonal carcinoma cells, Grainger et al. (2013) showed that Cdx2 was significantly less potent in transactivating the Cdx1 promoter compared with Cdx1. Further analysis revealed that the difference in Cdx1 and Cdx2 transactivation ability was due to differences in their N-terminal transactivation sequences.
German et al. (1994) demonstrated by fluorescence in situ hybridization that the CDX3 gene is located on 13q12.3. The gene encoding another insulin-regulating transcription factor, ISL1 (600366), maps to 5q.
Drummond et al. (1997) assigned the human CDX2 gene to chromosome 13q12-q13 by PCR of rodent/human somatic hybrid DNA followed by fluorescence in situ hybridization.
In the human, another 'caudal' homeobox transcription factor, CDX4, has been identified and found to reside on the X chromosome (300025). The gene is on the X chromosome in the mouse also.
Because the mouse homolog of CDX2 gives rise to a phenotype that includes hamartomatous-like polyps in the colon, Woodford-Richens et al. (2001) considered the gene to be a good candidate for cases of Peutz-Jeghers syndrome (PJS; 175200), juvenile polyposis syndrome (JPS; 174900), and sporadic colorectal cancer. They screened 37 JPS families/cases without known SMAD4 (600993) mutations, 10 PJS families/cases without known LKB1 (602216) mutations, and 49 sporadic colorectal cancers for mutations in the CDX2 gene. No pathogenic CDX2 mutations were found in any of these cases.
In Drosophila, disturbing the expression of the homeobox gene 'caudal' causes a severe disruption in body segmentation and global body patterning. In the mouse, 3 homologs of Drosophila 'caudal' were identified: Cdx1, Cdx2, and Cdx4 (300025). By homologous recombination in embryonic stem (ES) cells, Chawengsaksophak et al. (1997) generated a null mutation of murine Cdx2. Homozygote null mutants died between 3.5 and 5.5 days postcoitum. Heterozygous mutants exhibited a variable phenotype, with many showing tail abnormalities or stunted growth. Skeletal analysis demonstrated a homeotic shift of vertebrae and compatible malformations of the ribs. Within the first 3 months of life, 90% of Cdx2 heterozygotes developed multiple intestinal adenomatous polyps, particularly in the proximal colon. These polyps occasionally contained areas of true metaplasia. In contrast to the surrounding intestinal epithelium, the neoplastic cells did not express Cdx2 from the remaining allele. These results suggested that Cdx2 mutation is the primary event in the genesis of these intestinal tumors, a 2-hit phenomenon having been involved in their pathogenesis.
Mice heterozygous for knockout of the Cdx2 gene develop 1 or 2 benign hamartomas in the proximal colon, whereas mice heterozygous for deletion of amino acid residue 716 of Apc (611731) develop numerous adenomatous polyps, mostly in the small intestine. Aoki et al. (2003) showed that the colonic polyp number was about 6 times higher in mice who were compound heterozygotes for both mutations. The levels of both Apc and Cdx2 were significantly lower in the distal colon, which caused high anaphase bridge index (ABI) associated with a higher frequency of loss of heterozygosity (LOH) at Apc. Other experiments suggested that reduced expression of Cdx2 is important in colon tumorigenesis through the mTOR pathway.
Savory et al. (2009) found that knockin mice in which Cdx2 replaced Cdx1 were viable and fertile, with the mutant allele transmitted at a mendelian frequency. The mutant mice had no overt skeletal abnormalities and no vertebral patterning defects. The authors generated transgenic mice with a gain of function to alter Cdx1 dosage while maintaining the regulatory circuit implicated in Cdx1 expression. The Cdx1 gain of function complemented Cdx1 loss of function in mice and had no impact on vertebral patterning, indicating that a moderate alteration in the Cdx protein gradient was of no consequence. The authors concluded that Cdx1 and Cdx2 are functionally equivalent in vertebral patterning.
Using a 'gene swap' approach in mice, Grainger et al. (2013) found that Cdx2 could not drive expression from the Cdx1 promoter and was not efficiently expressed in small intestine to complement loss of endogenous Cdx2. Residual Cdx2 protein only partially supported Cdx2-dependent function in small intestine and did not support intestinal development or colon homeostasis. The authors concluded that Cdx1 and Cdx2 exhibit transcriptional specificity in intestine.
The gene that has been called Cdx2 in the mouse was formerly designated CDX3 in the human. The mouse Cdx2 gene maps to chromosome 5, in a region homologous to the human 13q12.3, where CDX2 is located.
Deb et al. (2006) reported that the transcription factor Cdx2 is expressed in the nuclei of cells derived from the late-dividing but not the first-dividing blastomere of 2-cell embryos and, by lineage tracing and RNA interference knockdown experiments, that this lagging cell is the precursor of trophectoderm. However, the editor-in-chief of Science stated that the results of the report may not be reliable (Kennedy, 2006). Vogel (2006) stated that the senior author of the report doubted the validity of the findings and predicted that the paper would be retracted. Roberts et al. (2007) retracted the paper by Deb et al. (2006) due to research misconduct involving the first author of the paper by intentionally falsifying and fabricating digital images in the preparation of several figures.
Aoki, K., Tamai, Y., Horiike, S., Oshima, M., Taketo, M. M. Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc(+/delta716) Cdx2(+/-) compound mutant mice. Nature Genet. 35: 323-330, 2003. [PubMed: 14625550] [Full Text: https://doi.org/10.1038/ng1265]
Chawengsaksophak, K., de Graaff, W., Rossant, J., Deschamps, J., Beck, F. Cdx2 is essential for axial elongation in mouse development. Proc. Nat. Acad. Sci. 101: 7641-7645, 2004. [PubMed: 15136723] [Full Text: https://doi.org/10.1073/pnas.0401654101]
Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F., Beck, F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386: 84-87, 1997. [PubMed: 9052785] [Full Text: https://doi.org/10.1038/386084a0]
Deb, K., Sivaguru, M., Yong, H. Y., Roberts, R. M. Cdx2 gene expression and trophectoderm lineage specification in mouse embryos. Science 311: 992-996, 2006. Note: Retraction: Science 317: 450 only, 2007. [PubMed: 16484492] [Full Text: https://doi.org/10.1126/science.1120925]
Drummond, F., Putt, W., Fox, M., Edwards, Y. H. Cloning and chromosome assignment of the human CDX2 gene. Ann. Hum. Genet. 61: 393-400, 1997. [PubMed: 9459001] [Full Text: https://doi.org/10.1046/j.1469-1809.1997.6150393.x]
German, M. S., Wang, J., Fernald, A. A., Espinosa, R., III, Le Beau, M. M., Bell, G. I. Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13. Genomics 24: 403-404, 1994. [PubMed: 7698771] [Full Text: https://doi.org/10.1006/geno.1994.1639]
Grainger, S., Hryniuk, A., Lohnes, D. Cdx1 and Cdx2 exhibit transcriptional specificity in the intestine. PLoS One 8: e54757, 2013. [PubMed: 23382958] [Full Text: https://doi.org/10.1371/journal.pone.0054757]
Gregory, P. A., Gardner-Stephen, D. A., Rogers, A., Michael, M. Z., Mackenzie, P. I. The caudal-related homeodomain protein Cdx2 and hepatocyte nuclear factor 1-alpha cooperatively regulate the UDP-glucuronosyltransferase 2B7 gene promoter. Pharmacogenet. Genomics 16: 527-536, 2006. [PubMed: 16788384] [Full Text: https://doi.org/10.1097/01.fpc.0000215068.06471.35]
Kennedy, D. Editorial expression of concern. (Letter) Science 314: 592 only, 2006. [PubMed: 17068242] [Full Text: https://doi.org/10.1126/science.314.5799.592b]
Meissner, A., Jaenisch, R. Generation of nuclear transfer-derived pluripotent ES cells from the cloned Cdx2-deficient blastocysts. Nature 439: 212-215, 2006. [PubMed: 16227971] [Full Text: https://doi.org/10.1038/nature04257]
Roberts, R. M., Sivaguru, M., Yong, H. Y. Retraction. (Letter) Science 317: 450 only, 2007. [PubMed: 17656701] [Full Text: https://doi.org/10.1126/science.317.5837.450b]
Savory, J. G. A., Pilon, N., Grainger, S., Sylvestre, J.-R., Beland, M., Houle, M., Oh, K., Lohnes, D. Cdx1 and Cdx2 are functionally equivalent in vertebral patterning. Dev. Biol. 330: 114-122, 2009. [PubMed: 19328777] [Full Text: https://doi.org/10.1016/j.ydbio.2009.03.016]
Vogel, G. Fraud investigation clouds paper on early cell fate. Science 314: 1367-1369, 2006. [PubMed: 17138872] [Full Text: https://doi.org/10.1126/science.314.5804.1367]
Woodford-Richens, K. L., Halford, S., Rowan, A., Bevan, S., Aaltonen, L. A., Wasan, H., Bicknell, D., Bodmer, W. F., Houlston, R. S., Tomlinson, I. P. M. CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers syndrome and occur infrequently in sporadic colorectal cancers. Brit. J. Cancer 84: 1314-1316, 2001. [PubMed: 11355940] [Full Text: https://doi.org/10.1054/bjoc.2001.1800]