Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes

Abstract

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, we have inactivated the gene via homologous recombination. Viable fertile homozygous mutant mice were obtained that show anterior homeotic transformations of vertebrae. These abnormalities were concomitant with posterior shifts of Hox gene expression domains in the somitic mesoderm. 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.

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

“…The phenotype of Cdx1 À/À mice has already been reported, except for the gut (Subramanian et al, 1995), and we confirmed here the loss of Cdx1 expression in the intestinal epithelium by reverse transcription (RT)-PCR and immunohistochemistry ( Figure 1). Next, we produced Vil-Cdx1 transgenic mice (lines no.…”

“…In conclusion, despite its important role in anteroposterior patterning of the body axis (Subramanian et al, 1995) Cdx1 is dispensable for intestinal development and homeostasis. During intestinal carcinogenesis, Cdx1 overexpression may increase the severity of malignancy at least transiently at early stages in the case of small intestinal tumours, before being lost in advanced tumours by promoter hypermethylation and allelic loss (Domon-Dell et al, 2003;Pilozzi et al, 2004).…”

“…The protein increases along the gut length, being restricted to the crypts in the small intestine and expressed in the bottom four-fifths of the colonic glands . Although the role of Cdx1 has been unveiled in body axis patterning (Subramanian et al, 1995), its relevance remains elusive in the gut. In intestinal cells cultured in vitro, Cdx1 stimulates differentiation (Soubeyran et al, 1999) and either stimulates (Lorentz et al, 1997;Soubeyran et al, 1999) or inhibits proliferation (Lynch et al, 2000).…”

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

“…The caudal-type transcription factors interact with HOX genes to generate the anterior-posterior axis, and viable homozygous cdx1 knockout mice were shown to have anterior homeotic transformations of vertebrae concomitant with posterior shifts of hox gene expression in the somatic mesoderm. 24 The effect of haploinsufficiency of this gene in humans is not known but altered precise temporal and spatial expression of genes such as the HOX genes during embryonic development is required for accurate skeletal modelling. 25 Unfortunately, material was not available for aCGH to identify the true extent of the deletions beyond the first exon in these patients.…”

“…In the other two cases the deletion extended into the 3¢-UTR, and may therefore extend into downstream genes. Patient 8 presented with dysmorphic features consistent with a diagnosis of TCS, and was shown to have a deletion of exons [23][24][25][26], that removes the C-terminal region of treacle important for localisation to the nucleolus. Array CGH analysis suggested that the deletion did not extend into the downstream CD74 gene.…”