Response: Cell fate in the early mouse embryo--sorting out the influence of developmental history on lineage choice.

The first three cell lineages formed in the implanting mouse embryo are the epiblast (EPI), primitive endoderm (PE) and trophectoderm. The EPI and PE are the two lineages derived from the inner cell mass (ICM) of the blastocyst, which give rise to the fetus and extraembryonic yolk sac, respectively. Previous studies suggest that embryonic day 3.5 ICM cells begin as a mixture of PE or EPI progenitors randomly distributed in the ICM which then sort out during blastocyst expansion to form two morphologically distinct layers. How are these two progenitors first specified? A proposed model is that the divisional history of ICM cells affects EPI/PE lineage specification. Two independent research groups addressed this issue using completely different approaches and reached different conclusions (Morris et al., 2010; Yamanaka et al., 2010). What causes the apparent discrepancy between the two studies? This commentary highlights two important differences in the design of the two studies: the timing of EPI/PE lineage evaluation and the strategy for scoring the results. It is proposed that these studies are not in conflict, but rather are complementary.