Wicklow Eryn, Blij Stephanie, Frum Tristan, Hirate Yoshikazu, Lang Richard A, Sasaki Hiroshi, Ralston Amy
Molecular, Cell, and Developmental Biology, University of California Santa Cruz, Santa Cruz, California, United States of America.
Institute of Molecular Embryology and Genetics, Kumamoto University, Chuo-ku, Kumamoto, Japan.
PLoS Genet. 2014 Oct 23;10(10):e1004618. doi: 10.1371/journal.pgen.1004618. eCollection 2014 Oct.
Pluripotent epiblast (EPI) cells, present in the inner cell mass (ICM) of the mouse blastocyst, are progenitors of both embryonic stem (ES) cells and the fetus. Discovering how pluripotency genes regulate cell fate decisions in the blastocyst provides a valuable way to understand how pluripotency is normally established. EPI cells are specified by two consecutive cell fate decisions. The first decision segregates ICM from trophectoderm (TE), an extraembryonic cell type. The second decision subdivides ICM into EPI and primitive endoderm (PE), another extraembryonic cell type. Here, we investigate the roles and regulation of the pluripotency gene Sox2 during blastocyst formation. First, we investigate the regulation of Sox2 patterning and show that SOX2 is restricted to ICM progenitors prior to blastocyst formation by members of the HIPPO pathway, independent of CDX2, the TE transcription factor that restricts Oct4 and Nanog to the ICM. Second, we investigate the requirement for Sox2 in cell fate specification during blastocyst formation. We show that neither maternal (M) nor zygotic (Z) Sox2 is required for blastocyst formation, nor for initial expression of the pluripotency genes Oct4 or Nanog in the ICM. Rather, Z Sox2 initially promotes development of the primitive endoderm (PE) non cell-autonomously via FGF4, and then later maintains expression of pluripotency genes in the ICM. The significance of these observations is that 1) ICM and TE genes are spatially patterned in parallel prior to blastocyst formation and 2) both the roles and regulation of Sox2 in the blastocyst are unique compared to other pluripotency factors such as Oct4 or Nanog.
多能性上胚层（EPI）细胞存在于小鼠囊胚的内细胞团（ICM）中，是胚胎干细胞（ES）和胎儿的祖细胞。探索多能性基因如何调控囊胚中的细胞命运决定，为理解多能性的正常建立提供了一条有价值的途径。EPI细胞是通过两个连续的细胞命运决定而特化形成的。第一个决定将ICM与滋养外胚层（TE）分离，TE是一种胚外细胞类型。第二个决定将ICM进一步细分为EPI和原始内胚层（PE），PE也是一种胚外细胞类型。在此，我们研究了多能性基因Sox2在囊胚形成过程中的作用和调控机制。首先，我们研究了Sox2模式的调控，发现SOX2在囊胚形成之前被HIPPO信号通路的成员限制在ICM祖细胞中，这一过程独立于CDX2，CDX2是将Oct4和Nanog限制在ICM中的TE转录因子。其次，我们研究了Sox2在囊胚形成过程中细胞命运特化中的需求。我们发现，母源（M）和合子（Z）来源的Sox2对于囊胚形成以及ICM中多能性基因Oct4或Nanog的初始表达都不是必需的。相反，合子来源的Sox2最初通过FGF4非细胞自主性地促进原始内胚层（PE）的发育，随后维持ICM中多能性基因的表达。这些观察结果的意义在于：1）在囊胚形成之前，ICM和TE基因在空间上平行模式化；2）与其他多能性因子如Oct4或Nanog相比，Sox2在囊胚中的作用和调控都是独特 的。
