Jedrusik Agnieszka, Parfitt David-Emlyn, Guo Guoji, Skamagki Maria, Grabarek Joanna B, Johnson Martin H, Robson Paul, Zernicka-Goetz Magdalena
Wellcome Trust/Cancer Research UK Gurdon Institute, Cambridge CB2 1QN, United Kingdom.
Genes Dev. 2008 Oct 1;22(19):2692-706. doi: 10.1101/gad.486108.
Genesis of the trophectoderm and inner cell mass (ICM) lineages occurs in two stages. It is initiated via asymmetric divisions of eight- and 16-cell blastomeres that allocate cells to inner and outer positions, each with different developmental fates. Outside cells become committed to the trophectoderm at the blastocyst stage through Cdx2 activity, but here we show that Cdx2 can also act earlier to influence cell allocation. Increasing Cdx2 levels in individual blastomeres promotes symmetric divisions, thereby allocating more cells to the trophectoderm, whereas reducing Cdx2 promotes asymmetric divisions and consequently contribution to the ICM. Furthermore, both Cdx2 mRNA and protein levels are heterogeneous at the eight-cell stage. This heterogeneity depends on cell origin and has developmental consequences. Cdx2 expression is minimal in cells with unrestricted developmental potential that contribute preferentially to the ICM and is maximal in cells with reduced potential that contribute more to the trophectoderm. Finally, we describe a mutually reinforcing relationship between cellular polarity and Cdx2: Cdx2 influences cell polarity by up-regulating aPKC, but cell polarity also influences Cdx2 through asymmetric distribution of Cdx2 mRNA in polarized blastomeres. Thus, divisions generating inside and outside cells are truly asymmetric with respect to cell fate instructions. These two interacting effects ensure the generation of a stable outer epithelium by the blastocyst stage.
滋养外胚层和内细胞团（ICM）谱系的发生分为两个阶段。它始于8细胞和16细胞卵裂球的不对称分裂，这些分裂将细胞分配到内部和外部位置，每个位置具有不同的发育命运。外部细胞在囊胚阶段通过Cdx2活性定向分化为滋养外胚层，但我们在此表明Cdx2也可以更早发挥作用来影响细胞分配。增加单个卵裂球中的Cdx2水平会促进对称分裂，从而将更多细胞分配到滋养外胚层，而降低Cdx2则会促进不对称分裂，进而增加对内细胞团的贡献。此外，在8细胞阶段，Cdx2的mRNA和蛋白质水平都是异质的。这种异质性取决于细胞来源并具有发育后果。Cdx2在具有优先向内细胞团贡献的无限制发育潜能的细胞中表达最低，而在具有降低的潜能且对滋养外胚层贡献更大的细胞中表达最高。最后，我们描述了细胞极性与Cdx2之间的相互增强关系：Cdx2通过上调非典型蛋白激酶C（aPKC）来影响细胞极性，但细胞极性也通过Cdx2 mRNA在极化卵裂球中的不对称分布来影响Cdx2。因此，就细胞命运指令而言，产生内部和外部细胞的分裂是真正不对称的。这两种相互作用的效应确保在囊胚阶段产生稳定的外层上皮。
