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 is 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.
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]
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]
CDX2 is also used in diagnostic surgical pathology as a marker for gastrointestinal differentiation, especially colorectal. [17]
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]
CDX2 has been shown to interact with EP300, [21] and PAX6. [21]
The ParaHox gene cluster is an array of homeobox genes from the Gsx, Xlox (Pdx) and Cdx gene families.
PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.
Homeobox protein Hox-A10 is a protein that in humans is encoded by the HOXA10 gene.
Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
Homeobox protein Hox-B4 is a protein that in humans is encoded by the HOXB4 gene.
Homeobox protein Hox-C8 is a protein that in humans is encoded by the HOXC8 gene.
Homeobox protein Hox-A13 is a protein that in humans is encoded by the HOXA13 gene.
Homeobox protein Hox-B9 is a protein that in humans is encoded by the HOXB9 gene.
Homeobox protein Hox-C6 is a protein that in humans is encoded by the HOXC6 gene. Hox-C6 expression is highest in the fallopian tube and ovary. HoxC6 has been highly expressed in many types of cancers including prostate, breast, and esophageal squamous cell cancer.
Paired related homeobox 1 is a protein that in humans is encoded by the PRRX1 gene.
Homeobox protein CDX-1 is a protein in humans that is encoded by the CDX1 gene. CDX1 is expressed in the developing endoderm and its expression persists in the intestine throughout adulthood. CDX1 protein expression varies along the intestine, with high expression in intestinal crypts and diminishing expression along intestinal villi.
Homeobox protein Hox-B8 is a protein that in humans is encoded by the HOXB8 gene.
The Cdx protein family is a group of the transcription factor proteins which bind to DNA to regulate the expression of genes. In particular this family of proteins can regulate the Hox genes. They are regulators of embryonic development and hematopoiesis in vertebrates, and are also involved in the development of some types of gastrointestinal cancers and leukemias.
Homeobox protein Nkx-6.1 is a protein that in humans is encoded by the NKX6-1 gene.
The Cdx gene family, also called caudal genes, are a group of genes found in many animal genomes. Cdx genes contain a homeobox DNA sequence and code for proteins that act as transcription factors. The gene after which the gene family is named is the caudal or cad gene of the fruitfly Drosophila melanogaster. The human genome has three Cdx genes, called CDX1, CDX2 and CDX4. The zebrafish has no cdx2 gene, but two copies of cdx1 and one copy of cdx4. The Cdx gene in the nematode Caenorhabditis elegans is called pal-1.
Homeobox protein CDX-4 is a protein that in humans is encoded by the CDX4 gene. This gene is a member of the caudal-related homeobox transcription factor family that also includes CDX1 and CDX2.