Nishioka Noriyuki, Yamamoto Shinji, Kiyonari Hiroshi, Sato Hiroko, Sawada Atsushi, Ota Mitsunori, Nakao Kazuki, Sasaki Hiroshi
Laboratory for Embryonic Induction, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo, Kobe, Hyogo 650-0047, Japan.
Mech Dev. 2008 Mar-Apr;125(3-4):270-83. doi: 10.1016/j.mod.2007.11.002. Epub 2007 Nov 17.
During pre-implantation mouse development, embryos form blastocysts with establishment of the first two cell lineages: the trophectoderm (TE) which gives rise to the placenta, and the inner cell mass (ICM) which will form the embryo proper. Differentiation of TE is regulated by the transcription factor Caudal-related homeobox 2 (Cdx2), but the mechanisms which act upstream of Cdx2 expression remain unknown. Here we show that the TEA domain family transcription factor, Tead4, is required for TE development. Tead1, Tead2 and Tead4 were expressed in pre-implantation embryos, and at least Tead1 and Tead4 were expressed widely in both TE and ICM lineages. Tead4-/- embryos died at pre-implantation stages without forming the blastocoel. The mutant embryos continued cell proliferation, and adherens junction and cell polarity were not significantly affected. In Tead4-/- embryos, Cdx2 was weakly expressed at the morula stage but was not expressed in later stages. None of the TE specific genes, including Eomes and a Cdx2 independent gene, Fgfr2, was detected in Tead4-/- embryos. Instead, the ICM specific transcription factors, Oct3/4 and Nanog, were expressed in all the blastomeres. Tead4-/- embryos also failed to differentiate trophoblast giant cells when they were cultured in vitro. ES cells with normal in vitro differentiation abilities were established from Tead4-/- embryos. These results suggest that Tead4 has a distinct role from Tead1 and Tead2 in trophectoderm specification of pre-implantation embryos, and that Tead4 is an early transcription factor required for specification and development of the trophectoderm lineage, which includes expression of Cdx2.
在植入前小鼠发育过程中，胚胎形成囊胚，并建立起最初的两个细胞谱系：产生胎盘的滋养外胚层（TE）和形成胚胎本体的内细胞团（ICM）。TE的分化受转录因子尾相关同源盒2（Cdx2）调控，但Cdx2表达上游的作用机制尚不清楚。在这里，我们表明TEA结构域家族转录因子Tead4是TE发育所必需的。Tead1、Tead2和Tead4在植入前胚胎中表达，并且至少Tead1和Tead4在TE和ICM谱系中广泛表达。Tead4基因敲除胚胎在植入前阶段死亡，未形成囊胚腔。突变胚胎继续进行细胞增殖，黏附连接和细胞极性未受到显著影响。在Tead-/-胚胎中，Cdx2在桑椹胚阶段弱表达，但在后期不表达。在Tead4-/-胚胎中未检测到任何TE特异性基因，包括Eomes和一个不依赖Cdx2的基因Fgfr2。相反，ICM特异性转录因子Oct3/4和Nanog在所有卵裂球中表达。当Tead4-/-胚胎在体外培养时，它们也无法分化为滋养层巨细胞。从Tead4-/-胚胎中建立了具有正常体外分化能力的胚胎干细胞。这些结果表明，Tead4在植入前胚胎的滋养外胚层特化中具有与Tead1和Tead2不同的作用，并且Tead4是滋养外胚层谱系特化和发育所必需的早期转录因子，这包括Cdx2的表达。
