Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst

Abstract

Blastocyst formation marks the segregation of the first two cell lineages in the mammalian preimplantation embryo: the inner cell mass (ICM) that will form the embryo proper and the trophectoderm (TE) that gives rise to the trophoblast lineage. Commitment to ICM lineage is attributed to the function of the two transcription factors, Oct4 (encoded by Pou5f1) and Nanog. However, a positive regulator of TE cell fate has not been described. The T-box protein eomesodermin (Eomes) and the caudal-type homeodomain protein Cdx2 are expressed in the TE, and both Eomes and Cdx2homozygous mutant embryos die around the time of implantation. A block in early TE differentiation occurs in Eomes mutant blastocysts. However, Eomes mutant blastocysts implant, and Cdx2 and Oct4expression are correctly restricted to the ICM TE. Blastocoel formation initiates in Cdx2 mutants but epithelial integrity is not maintained and embryos fail to implant. Loss of Cdx2 results in failure to downregulate Oct4 and Nanog in outer cells of the blastocyst and subsequent death of those cells. Thus, Cdx2 is essential for segregation of the ICM and TE lineages at the blastocyst stage by ensuring repression of Oct4 and Nanog in the TE.

Negative autoregulation of Oct3/4 through Cdx1 promotes the onset of gastrulation

“…Another regulatory network involving Oct3/4 and a Cdx gene has been described in mouse embryos during trophectodermal differentiation (Niwa et al, 2005;Strumpf et al, 2005;Tolkunova et al, 2006). In this case, Cdx2 represses the expression of Oct3/4 in trophoblast cells, similar to our case in which Cdx1 represses the expression of the Pou5f1 genes with the transition into gastrulation.…”

Cell and molecular regulation of the mouse blastocyst

“…Molecularly, TE and ICM lineages can be distinguished by the expression patterns of several lineage-specific transcription factors. Cdx2, which is related to Drosophila Caudal, is expressed in the TE of the blastocyst where it is required for promoting TE fate (Beck et al, 1995;Strumpf et al, 2005). Two ICMspecific transcription factors are Oct4, a POU domain protein, and Nanog, a homeodomain protein (Palmieri et al, 1994;Chambers et al, 2003;Mitsui et al, 2003).…”

“…Furthermore, Oct4 protein is not detectable in nuclei A gene important for early TE development also has been identified. Cdx2 encodes a Caudal-like transcription factor and is expressed in the TE of the blastocyst (Beck et al, 1995;Strumpf et al, 2005). Cdx2 protein is first detectable in the nuclei of select cells at the eight-cell stage (Niwa et al, 2005) and becomes restricted to outer cells of the late morula (Niwa et al, 2005;Strumpf et al, 2005).…”

“…Cdx2 encodes a Caudal-like transcription factor and is expressed in the TE of the blastocyst (Beck et al, 1995;Strumpf et al, 2005). Cdx2 protein is first detectable in the nuclei of select cells at the eight-cell stage (Niwa et al, 2005) and becomes restricted to outer cells of the late morula (Niwa et al, 2005;Strumpf et al, 2005). Cdx2 mutant embryos form a normal-appearing blastocyst, although ICM markers such as Oct4 and Nanog fail to be repressed in the TE , indicating a defect in restriction of the ICM/TE lineage.…”

L’embryogenèse précoce des mammifères

“…Ces protéines impliquées dans la polarité cellulaire influencent donc la position de la cellule dans l'embryon, mais cependant ne lui donnent pas une identité définitive. L'identité trophoblastique est fixée entre les stades 32 et 64 cellules (début de la formation du blastocyste) et peut être visualisée grâce à l'expression sélective du facteur de transcription Cdx2 dans les cellules externes [13][14][15][16]. À l'inverse, celle des gènes de pluripotence tels que Oct-4, Sox2 et Nanog est restreinte aux cellules internes du blastocyste.…”