CDX2 in Congenital Gut Gastric-Type Heteroplasia and Intestinal-Type Meckel Diverticula

Abstract

The mechanisms that determine organ identity along the digestive tract in humans are poorly understood. Here we describe the rare case of a young patient who presented with congenital gastric-type heteroplasia in the midjejunum. The lesions, located along the antimesenteric midline of the gut, were made of histologically and functionally normal gastric epithelium without inflammation or in situ/invasive carcinoma. They resembled the anatomy of the lesions developing in the mouse gut as a result of haploinsufficiency of the Cdx2 homeobox gene. The lesions were devoid of CDX2 but without mutation in the coding sequence or in a cis-regulatory element required for intestine-specific expression. Combining these data with the CDX2 expression pattern established from human embryos and cases of Meckel diverticula, we propose a scenario for this patient's presentation, in which CDX2 was missing at the site of ventral closure during gut morphogenesis, with subsequent default differentiation into gastric instead of intestinal tissue. Altogether, these observations argue in favor of a pivotal role played by CDX2 in determining intestinal identity during human embryonic development, as previously shown experimentally in mice.

Meckel’s Diverticulum in Children: A Monocentric Experience and Mini-Review of Literature

“…In addition, they hypothesized that the Cdx2-homebox transcription factor might play a pivotal role in determining the intestinal epithelial phenotype during embryogenic development, a mechanism possibly accounting for the prominence of male gender in heterotopic MD. In this context, Martin et al described a case of absent Cdx2 expression in congenital gastric-type heteroplasia in the mid-jejunum of an eight years old male, which was similar to the gastric heteroplasia in the developing gut endoderm observed in a murine model with loss of function of the homeobox gene Cdx2 [ 10 ]. Moreover, as observed in gastric cancer patients, methylation of Cdx2 with consecutive downregulation of gene expression is predominantly found to be increased in males, possibly being ascribed to gender-specific host factors such as estrogens [ 11 ].…”

A Core Response to the CDX2 Homeoprotein During Development and in Pathologies

“…However, human CDX2 gene variants have recently been associated with sirenomelia ( Lecoquierre et al, 2020 ), in accordance with the function attributed to this gene in posterior body elongation and patterning. Moreover, the aberrant expression of CDX2 reported in various forms of congenital endoderm-derived heteroplasia corroborates its key role in intestinal identity determination ( Martin et al, 2010 ). Beyond embryogenesis, pathological alterations of CDX2 levels occur at its physiological site of expression, the gut, as well as ectopically in the upper digestive tract and in leukemia.…”

BioData Mining | Short Report (Biomedcentral.Com) Combinatorial Analyses Identify A Core Response to the CDX2 Homeoprotein During Development and In Pathologies

“…The combinatorial analyses of data from mouse embryonic developmental have identi ed cores of common differentially-expressed genes and chromatin regions responsive to the Cdx2 homeoprotein at three steps where this transcription factor plays pivotal roles: trophectoderm differentiation, posterior growth of the embryonic body and intestinal determination. Similar functions are anticipated for the CDX2 gene in human embryonic development, because of its speci c expression in the trophectoderm lineage at the blastula stage [35], the association of gene mutations with sirenomelia [33], and its abnormal expression linked to gut-type differentiation in congenital endoderm-derived lesions [34].…”