HGNC Approved Gene Symbol: CDX1
Cytogenetic location: 5q32 Genomic coordinates (GRCh38): 5:150,166,778-150,184,558 (from NCBI)
CDX1 is a member of the caudal-type homeobox family of genes. These are cognates of the Drosophila 'caudal' gene, which is required for anterior-posterior regional identity. Homologous genes have been found in mouse, rat, chicken, and Xenopus. CDX3 (CDX2; 600297) is the human caudal-type homeobox gene located on chromosome 13. The caudal-type homeobox genes are members of the hexapeptide (HEX) superclass, containing a conserved hexapeptide motif upstream of the homeodomain, usually separated from the homeodomain by an intron (Bonner et al., 1995).
Bonner et al. (1995) isolated the human CDX1 gene from a small intestine cDNA library using a murine Cdx1 cDNA probe. The nucleotide sequence of CDX1 was 81% identical to murine Cdx1 and predicted a 265-amino acid protein with 85% identity to the mouse protein (or 98% identity when the conservative amino acid changes were included). Northern analysis indicated that expression of CDX1 in adults appears to be limited to the intestine and colon, suggesting a possible role in the terminal differentiation of the intestine.
In the mouse, Cdx1 is expressed along the embryonic axis from day 7.5 postcoitum until day 12, by which time the anterior limit of expression has regressed from the hindbrain level to the forelimb bud region. To assign a functional role for Cdx1 in murine embryonic development, Subramanian et al. (1995) inactivated the gene via homologous recombination. Viable fertile homozygous mutant mice were obtained that showed anterior homeotic transformations of vertebrae. These abnormalities were concomitant with posterior shifts of Hox gene expression domains in the somitic mesoderm. The authors stated that the presence of putative Cdx1-binding sites in Hox gene control regions as well as in vitro transactivation of Hoxa7 indicates a direct regulation.
In endoscopic tissue biopsies, Wong et al. (2005) found that CDX1 mRNA and protein were universally expressed in all samples of Barrett metaplasia (BM; see 109350) tested but not in normal esophageal squamous or gastric body epithelia. They attributed this tissue-specific expression pattern to the methylation status of the CDX1 promoter, which was completely methylated in normal squamous and gastric epithelia but demethylated in a majority of DNA clones from BM tissue. Conjugated bile salts and the inflammatory cytokines TNF-alpha (191160) and IL1-beta (147720) increased CDX1 mRNA expression via the NF-kappa-B (see 164011) pathway in vitro, but only when the CDX1 promoter was unmethylated or partially methylated. Wong et al. (2005) suggested that CDX1 is the molecular link between the etiologic agents that cause BM and the induction of an intestinal phenotype, and that CDX1 promoter demethylation is the key trigger for the development of BM.
Ryu et al. (2008) showed that in Drosophila the intestinal homeobox gene Caudal regulates the commensal-gut mutualism by repressing NF-kappa-B-dependent antimicrobial peptide genes. Inhibition of Caudal expression in flies via RNA interference led to overexpression of antimicrobial peptides, which in turn altered the commensal population within the intestine. In particular, the dominance of one gut microbe, Glucobacter sp. strain EW707, eventually led to gut cell apoptosis and host mortality. However, restoration of a healthy microbiota community and normal host survival in the Caudal-RNAi flies was achieved by reintroduction of the Caudal gene. Ryu et al. (2008) concluded that a specific genetic deficiency within a host can profoundly influence the gut commensal microbial community and host physiology.
Grainger et al. (2013) noted that CDX1 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.
The murine Cdx1 gene maps to mouse chromosome 18, near Csfmr and Pdgfrb, in a region of conserved synteny with human 5q31-q33. Bonner et al. (1995) demonstrated that the human cognate of Cdx1 maps to a cosmid contig from 5q31-q33, placing CDX1 approximately 100 kb distal to CSF1R (164770). (CSF1R had been mapped to 5q33.2-q33.3.)
In the course of positional cloning of the gene involved in the pathogenesis of Treacher Collins syndrome (154500), the Treacher Collins Syndrome Collaborative Group (1996) determined that the CDX1 locus is situated within a region of approximately 900 kb proximal to the TCOF1 gene (606847).
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.
Bonner, C. A., Loftus, S. K., Wasmuth, J. J. Isolation, characterization, and precise physical localization of human CDX1, a caudal-type homeobox gene. Genomics 28: 206-211, 1995. [PubMed: 8530027] [Full Text: https://doi.org/10.1006/geno.1995.1132]
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]
Ryu, J.-H., Kim, S.-H., Lee, H.-Y., Bai, J. Y., Nam, Y.-D., Bae, J.-W., Lee, D. G., Shin, S. C., Ha, E.-M., Lee, W.-J. Innate immune homeostasis by the homeobox gene Caudal and commensal-gut mutualism in Drosophila. Science 319: 777-782, 2008. [PubMed: 18218863] [Full Text: https://doi.org/10.1126/science.1149357]
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]
Subramanian, V., Meyer, B. I., Gruss, P. Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes. Cell 83: 641-653, 1995. [PubMed: 7585967] [Full Text: https://doi.org/10.1016/0092-8674(95)90104-3]
Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nature Genet. 12: 130-136, 1996. [PubMed: 8563749] [Full Text: https://doi.org/10.1038/ng0296-130]
Wong, N. A. C. S., Wilding, J., Bartlett, S., Liu, Y., Warren, B. F., Piris, J., Maynard, N., Marshall, R., Bodmer, W. F. CDX1 is an important molecular mediator of Barrett's metaplasia. Proc. Nat. Acad. Sci. 102: 7565-7570, 2005. [PubMed: 15894614] [Full Text: https://doi.org/10.1073/pnas.0502031102]