Dev Cell. 16:398-410, 2009

The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass.

Outside cells of the preimplantation mouse embryo form the trophectoderm (TE), a process requiring the transcription factor Tead4. Here, we show that transcriptionally active Tead4 can induce Cdx2 and other trophoblast genes in parallel in embryonic stem cells. In embryos, the Tead4 coactivator protein Yap localizes to nuclei of outside cells, and modulation of Tead4 or Yap activity leads to changes in Cdx2 expression. In inside cells, Yap is phosphorylated and cytoplasmic, and this involves the Hippo signaling pathway component Lats. We propose that active Tead4 promotes TE development in outside cells, whereas Tead4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization. Thus, differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation.

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CDBより。
●Tead4-Cdx2 pathwayによるTE分化制御について
●Tead4の発現はpan-embryonicなのに、なぜTEでのみ機能するか？

●Cell-cell contacts→Hippo→Lats1/2---|Yorkie/Yap1→Tead4経路活性化

●活性化型Tead4として、Tead4VP16を使用（いいのか？）
●Tead4haCdx2を含むTE細胞分化にかかわる因子群を制御（Fig1～2）
●核内YapとCdx2の発現がcorrelate、かつYapでCdx2の発現が制御される（Fig.3，4)
●Wwtr1（Yap-related)がcompensativeに機能
●Yap/Wwtr1のkinaseであるLats1/2がYapのリン酸化を介して核外排出を促進
●E-cadherin阻害剤のECCD1を用いると、Yapの核外排出とリン酸化が阻害されることから、ICMのcell-cell interactionが（Hippoを介して）Yapのリン酸化+核外排出に重要（Fig6)
●胚をばらしてreaggregateしたもの/immunosurgeryでICMだけ出してcultureしたもので、cell positionによってYapの核局在が規定されていることを証明（Fig7）
●モデル（Fig7)

Immunosurgeryについての文献は。
http://www.pnas.org/content/72/12/5099.full.pdf
http://media.wiley.com/product_data/excerpt/68/04700335/0470033568.pdf