Requirement for ERK MAP kinase in mouse preimplantation development

Preimplantation development is a crucial step for successful implantation and pregnancy. Although both compaction and blastocyst formation have been extensively studied, mechanisms regulating early cell division stages before compaction have remained unclear. Here, we show that ERK MAP kinase function is required for early embryonic cell division and normal cell-cell adhesion before compaction. Our analysis demonstrates that inhibition of ERK activation in the late 2-cell stage embryos leads to a reversible arrest in G2 phase in the 4-cell stage. The G2 arrested, 4-cell stage embryos show weakened cell-cell adhesion as compared to control embryos. Remarkably, microarray analyses show that most of the programmed changes of upregulated and downregulated gene expression during the 4- to 8-cell stages normally proceed in the 4-cell stage-arrested embryos, except for a portion of the genes whose expression profiles closely parallel the stages of embryonic development when arrested in G2 and released to resume development. These parallel genes include the genes encoding intercellular adhesion molecules, whose expression is found to be positively regulated by the ERK pathway. We also show that while ERK inactivation in the 8-cell stage embryos does not lead to cell division arrest, it does cause cell division arrest when cadherin-mediated cell-cell adhesion is disrupted. These results demonstrate an essential role of ERK function in the G2/M transition and the expression of adhesion molecules during the 2-cell to 8-cell stage embryos, and suggest a loose parallelism between the gene expression programs and the developmental stages before compaction.

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Maekawa M, Yamamoto T, Kohno M, Takeichi M, Nishida E