Homeobox protein CDX-2 is a
protein that in humans is encoded by the CDX2gene. The CDX-2 protein is a
homeoboxtranscription 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.
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
PMID7698771.
^
abBeck 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.
PMID8573715.
S2CID19576530.
Inoue H, Riggs AC, Tanizawa Y, Ueda K, Kuwano A, Liu L,
Donis-Keller H, Permutt MA (1 June 1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene". Diabetes. 45 (6): 789–794.
doi:
10.2337/diabetes.45.6.789.
PMID8635654.
Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Dagorn JC, Iovanna JL (Feb 1997). "Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis". International Journal of Cancer. 74 (1): 35–44.
doi:
10.1002/(SICI)1097-0215(19970220)74:1<35::AID-IJC7>3.0.CO;2-1.
PMID9036867.
S2CID46416077.
Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E (Feb 1999). "The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine". Journal of Bone and Mineral Research. 14 (2): 240–7.
doi:
10.1359/jbmr.1999.14.2.240.
PMID9933478.
S2CID45176819.
Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K (2002). "Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia". Journal of Gastroenterology. 37 (2): 94–100.
doi:
10.1007/s005350200002.
PMID11871772.
S2CID20514893.
Moucadel V, Totaro MS, Dell CD, Soubeyran P, Dagorn JC, Freund JN, Iovanna JL (Sep 2002). "The homeobox gene Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells". Biochemical and Biophysical Research Communications. 297 (3): 607–15.
doi:
10.1016/S0006-291X(02)02250-7.
PMID12270138.
Song BL, Qi W, Wang CH, Yang JB, Yang XY, Lin ZX, Li BL (Jan 2003). "Preparation of an anti-Cdx-2 antibody for analysis of different species Cdx-2 binding to acat2 promoter". Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica. 35 (1): 6–12.
PMID12518221.
Homeobox protein CDX-2 is a
protein that in humans is encoded by the CDX2gene. The CDX-2 protein is a
homeoboxtranscription 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.
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.
PMID7698771.
^
abBeck 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.
PMID8573715.
S2CID19576530.
Inoue H, Riggs AC, Tanizawa Y, Ueda K, Kuwano A, Liu L,
Donis-Keller H, Permutt MA (1 June 1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene". Diabetes. 45 (6): 789–794.
doi:
10.2337/diabetes.45.6.789.
PMID8635654.
Mallo GV, Rechreche H, Frigerio JM, Rocha D, Zweibaum A, Lacasa M, Jordan BR, Dusetti NJ, Dagorn JC, Iovanna JL (Feb 1997). "Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis". International Journal of Cancer. 74 (1): 35–44.
doi:
10.1002/(SICI)1097-0215(19970220)74:1<35::AID-IJC7>3.0.CO;2-1.
PMID9036867.
S2CID46416077.
Yamamoto H, Miyamoto K, Li B, Taketani Y, Kitano M, Inoue Y, Morita K, Pike JW, Takeda E (Feb 1999). "The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine". Journal of Bone and Mineral Research. 14 (2): 240–7.
doi:
10.1359/jbmr.1999.14.2.240.
PMID9933478.
S2CID45176819.
Eda A, Osawa H, Yanaka I, Satoh K, Mutoh H, Kihira K, Sugano K (2002). "Expression of homeobox gene CDX2 precedes that of CDX1 during the progression of intestinal metaplasia". Journal of Gastroenterology. 37 (2): 94–100.
doi:
10.1007/s005350200002.
PMID11871772.
S2CID20514893.
Moucadel V, Totaro MS, Dell CD, Soubeyran P, Dagorn JC, Freund JN, Iovanna JL (Sep 2002). "The homeobox gene Cdx1 belongs to the p53-p21(WAF)-Bcl-2 network in intestinal epithelial cells". Biochemical and Biophysical Research Communications. 297 (3): 607–15.
doi:
10.1016/S0006-291X(02)02250-7.
PMID12270138.
Song BL, Qi W, Wang CH, Yang JB, Yang XY, Lin ZX, Li BL (Jan 2003). "Preparation of an anti-Cdx-2 antibody for analysis of different species Cdx-2 binding to acat2 promoter". Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao Acta Biochimica et Biophysica Sinica. 35 (1): 6–12.
PMID12518221.