Disease relevance of Cdx1

• We used stable transfection of inducible constructs and transient expression with a replication-deficient adenovirus to induce Cdx1 expression in rat IEC6 cells, a non-transformed intestinal epithelial cell line that does not express Cdx1 protein [1].
• We conclude that Cdx1 reduces the proliferation of human colon cancer cells by reducing cyclin D1 gene transcription [2].
• Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo [3].
• Mice heterozygous for null mutations in the caudal-type homeobox gene Cdx2 show multiple adenomatous polyps in the proximal colon in addition to skeletal problems associated with abnormal segmentation [4].
• Whether disturbance of the regulation of Sox2 and Cdx genes may be of importance to the biological behavior of gastric cancers should therefore be clarified in future studies [5].

High impact information on Cdx1

• The presence of putative Cdx1-binding sites in Hox gene control regions as well as in vitro transactivation of Hoxa-7 indicates a direct regulation [6].
• Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes [6].
• To assign a functional role for Cdx1 in murine embryonic development, we have inactivated the gene via homologous recombination [6].
• 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 [6].
• The Cdx-1 gene is the first homeo-box-containing gene expressed in cells derived from the embryonic endoderm [7].

Biological context of Cdx1

• This autoregulation is reflected by the ability of Cdx1 to affect expression from proximal Cdx1 promoter sequences in tissue culture [8].
• The absence of Cdx1 function in Rb/p130 double mutant mice partially reverted the histologic phenotype by suppressing ectopic mitosis in the epithelium [9].
• Synergistic interactions between these null alleles were observed in compound mutants, and the full effects of exogenous RA on vertebral morphogenesis required Cdx1 [10].
• There is considerable evidence that the Cdx gene products impact on vertebral patterning by direct regulation of Hox gene expression [11].
• BACKGROUND & AIMS: The intestine-specific transcription factors Cdx1 and Cdx2 are candidate genes for directing intestinal development, differentiation, and maintenance of the intestinal phenotype [12].

Anatomical context of Cdx1

• Later, expression regresses from the anterior sclerotomes, and is only maintained for Cdx1 in the dorsal part of the somites, and for both genes in the tail bud [13].
• Cdx1 null mutants show anterior homeosis of upper cervical and thoracic vertebrae [13].
• 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 [12].
• Expression of Cdx1 increased from 13.5 to 14.5 pc during the endoderm/epithelial transition with predominately distal expression [12].
• The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins [1].

Associations of Cdx1 with chemical compounds

• Expression of Cdx1 is regulated by several pathways implicated in anterior-posterior patterning events, including retinoid and Wnt signaling [8].
• We have previously shown that retinoic acid plays a key role in early stages of Cdx1 expression at embryonic day 7.5 (E7.5), while both Wnt3a signaling and an autoregulatory loop, dependent on Cdx1 itself, are involved in later stages of expression (E8.5 to E9.5) [8].
• These findings are consistent with a role for RA upstream of Cdx1 as regards axial patterning [10].

Regulatory relationships of Cdx1

• Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo [14].
• Our analysis demonstrates that the early Cdx1 expression is regulated through the caudalizing Wnt/beta-catenin and RA activities [15].
• The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components [3].

Other interactions of Cdx1

• We have analysed the genetic interactions between Cdx1 and Cdx2 in compound mutants [13].
• Taken together, these results suggest that Cdx4, like Cdx1, is a direct Wnt target [11].
• We also found a direct physical interaction between the homeodomain of Cdx1 and the B box of LEF1, suggesting a basis for this synergy [8].
• We conclude that Cdx1 regulates intestinal epithelial cell proliferation by inhibiting progression through G(0)/G(1), most likely via modulation of cyclin D1 and D2 protein levels [1].
• The mouse Cdx1 gene encodes a homeobox-containing transcription factor and is one of the few homeobox genes known to be expressed in endodermally derived tissues of the intestine in fetal and adult mice [16].

Analytical, diagnostic and therapeutic context of Cdx1

• METHODS: Embryonic and postnatal mouse tissues were analyzed by immunohistochemistry to determine protein expression of Cdx1 and Cdx2 in the developing intestinal tract [12].
• Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded [14].
• Explants taken from specific regions of the gut and placed into organ culture develop and express molecular markers (Cdx1, Cdx2 and A33 antigen) in the same spatial and temporal pattern observed in vivo indicating that regional specification is maintained [17].
• 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 [18].

References