TheCdx4mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice

Abstract

Caudal related homeobox (Cdx) genes have so far been shown to be important for embryonic axial elongation and patterning in several vertebrate species. We have generated a targeted mutation of mouse Cdx4, the third member of this family of transcription factor encoding genes and the last one to be inactivated genetically. Cdx4-null embryos were born healthy and appeared morphologically normal. A subtle contribution of Cdx4 to anteroposterior (AP) vertebral patterning was revealed in Cdx1/Cdx4 and Cdx2/Cdx4 compound mutants. Neither Cdx4-null nor Cdx1/Cdx4 double mutants are impaired in their axial elongation, but a redundant contribution of Cdx4 in this function was unveiled when combined with a Cdx2 mutant allele. In addition, inactivation of Cdx4 combined with heterozygous loss of Cdx2 results in embryonic death around E10.5 and reveals a novel function of Cdx genes in placental ontogenesis. In a subset of Cdx2/Cdx4 compound mutants, the fully grown allantois failed to fuse with the chorion. The remaining majority of these mutants undergo successful chorio-allantois fusion but fail to properly extend their allantoic vascular network into the chorionic ectoderm and do not develop a functional placental labyrinth. We present evidence that Cdx4 plays a crucial role in the ontogenesis of the allantoic component of the placental labyrinth when one Cdx2 allele is inactivated. The axial patterning role of Cdx transcription factors thus extends posteriorly to the epiblast-derived extra-embryonic mesoderm and, consequent upon the evolution of placental mammals, is centrally involved in placental morphogenesis. The relative contribution of Cdx family members in the stepwise ontogenesis of a functional placenta is discussed, with Cdx2 playing an obligatory part, assisted by Cdx4. The possible participation of Cdx1 was not documented but cannot be ruled out until allelic combinations further decreasing Cdx dose have been analyzed. Cdx genes thus operate in a redundant way during placentogenesis, as they do during embryonic axial elongation and patterning, and independently from the previously reported early Cdx2-specific role in the trophectoderm at implantation.

The murine allantois: emerging paradigms in development of the mammalian umbilical cord and its relation to the fetus

“…Similar to VCAM1 and a4-integrin, single mutations in LPP3 (EscalanteAlcalde et al, 2003), Smad1 (Lechleider et al, 2001;Tremblay et al, 2001), Edd (Saunders et al, 2004), and Fibroblast growth factor receptor (Fgfr2) (Xu et al, 1998) are incompletely penetrant, with union absent in 20-70% of homozygous mutant conceptuses. Compound mutations in BMP5/BMP7 (Solloway and Robertson, 1999), Caudal-related homeodomain protein (Cdx2/ Cdx4) (van Nes, 2006;van Nes et al, 2006), and COOHterminal binding protein (Ctbp1/Ctbp2) (Hildebrand and Soriano, 2002) also display some degree of defective chorio-allantoic union, underscoring the role of multiple molecules in successful union.…”

Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model

“…Consensus binding sites for the three Cdx homologues Cdx1, Cdx2, and Cdx4 are present in the promoters of multiple Hox genes (2), and several lines of evidence highlight the importance of CDX family members as upstream regulators of HOX gene expression. These include a key role for CDX2 in regulation of HOX gene expression in the epithelium of the gastrointestinal tract (3), and similar homeotic transformations in Cdx1-, Cdx2-, and Cdx4-deficient mice and zebrafish to those observed in Hox-deficient animals (4,5).…”

Structure-Function Analysis of the Drosophila melanogaster Caudal Transcription Factor Provides Insights into Core Promoter-preferential Activation

“…1C). Notably, mCdx4, which differs from mCdx1 and mCdx2 (67,70,71), activated ftz transcription with core promoter specificity; however, the -fold difference between the activation of the two reporters by mCdx4 was not as pronounced as that observed with mCdx1 or mCdx2 (Fig. 1C).…”