Abstract
Embryos from inbred strains are sensitive to the stresses of culture in vitro compared to hybrid strains. This difference provides a powerful model for identifying genetic regulators of embryo viability in vitro. We showed that culture stress can cause the activation of the TRP53 stress response pathway, culminating in poor embryo viability.1 Directed genomic analysis of potential target genes was undertaken by comparing blastocysts cultured from zygotes of C57BL6.Trp53+/+, C57BL6.Trp53–/– and B6CBF2 genetic backgrounds. This comparison allowed genes with altered expression due to culture in susceptible strains to be identified and determined whether their changed expression was primarily due to the actions of TRP53. Culture had no effect on the expression of a number of house-keeping genes tested. Of known TRP53 target genes tested, only Bax showed a negative association with embryo viability. Interestingly, this was only partially reduced in C57BL6.Trp53–/–, indicating that other factors account for much of its up-regulation. Pluripotency genes showed a complex picture. Nanog was strongly negatively correlated with viability yet NANOG protein was strongly positively associated, indicating complex regulatory control; Oct4 showed no association yet OCT4 was strongly positively associated; Utf1 was the only pluripotency gene tested that showed Trp53 dependent down-regulation in cultured C57BL6.Trp53+/+. Markers of differentiation, Cdx2 (trophectodermal), Gata6 (endodermal) and Brachyury (mesodermal) did not differ between strains. The results identify Trp53-dependent alterations in gene expression in regulators of cell survival (Bax) and pluripotency (Utf1) that may account for the reduction in the capacity of susceptible blastocysts to form a proliferating inner cell mass. The study also identifies for the first time the possibility of complex post-transcriptional regulation of other pluripotency genes (Nanog and Oct4) that may shed future light on the regulation of pluripotency. (1) Li A, et al. Biol. Reprod. 2007; 76: 362–367.
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