In addition undergo phase variation between transparent variants

The high frequency of transgenic concepti without epiblast but retaining the hypoblast as well as the TE, indicates that the epiblast is most sensitive to cell death. The epiblast is derived from the ICM which segregates into the epiblast and hypoblast lineages at Day 8, as marked by exclusive expression of NANOG and GATA6 respectively. The survival of the hypoblast under conditions that lead to the loss of the epiblast, indicates firstly that these two ICM derived lineages show differential sensitivity to BAD overexpression. Secondly, one can conclude that the ICM itself does not undergo BAD-induced apoptosis prior to generating the two lineages. While the hypoblast is not lost, its gene expression profile is frequently changed upon BAD overexpression. A loss of GATA4 in hypoblast is likely to have severe developmental consequences based on mouse loss of function studies. On the other hand, FIBRONECTIN secretion by the hypoblast is likely to be required for interactions with the adjacent trophoblast. Notably the trophectoderm is refractory to BAD overexpression, as reflected by equal Axitinib 319460-85-0 proportions of recoveries of transgenic and wild type embryos and the normal expression of a trophoblast marker characteristic of Day13�C14 embryos. We suggest that the overexpression of BAD, similar to its effects in other systems, results in a sensitization of cells to trophic signals. Hence, in our experiments, the demise of the epiblast indicates insufficient signaling to inhibit the proapoptotic activity of increased BAD protein. BAD can be inactivated by phosphorylation, usually via AKT activation. AKT in turn is activated by PI3K which is the target of multiple receptors that respond to a range of trophic ligands. Interestingly, trophic signals, through AKT activation, not only inactivate BAD but also result in TP53 degradation. This similarly aids cell survival as TP53 enhances apoptosis by activating BAX. Notably, in an in vitro model of early mouse development, TP53 was implicated in a lineage specific effect of culture-induced stress. The Nutlin-3 authors cultured wild type zygotes for 96 hours in a culture medium deprived of trophic factors.

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