The role of the homeobox transcriptional repressor HESX1 in embryonic stem cells (ESCs) remains mostly unknown. Here, we show that Hesx1 is expressed in the preimplantation mouse embryo, where it is required during developmental diapause. Absence of Hesx1 leads to reduced expression of epiblast and primitive endoderm determinants and failure of diapaused embryos to resume embryonic development after implantation. Genetic deletion of Hesx1 impairs self-renewal and promotes differentiation toward epiblast by reducing the expression of pluripotency factors and decreasing the activity of LIF/STAT3 signaling. We reveal that Hesx1-deficient ESCs show elevated ERK pathway activation, resulting in accelerated differentiation toward primitive endoderm, which can be prevented by overexpression of Hesx1. Together, our data provide evidence for a novel role of Hesx1 in the control of self-renewal and maintenance of the undifferentiated state in ESCs and mouse embryos.

同源框转录抑制因子 HESX1 在胚胎干细胞 (ESC) 中的作用仍然知之甚少。在这里，我们发现Hesx1在植入前小鼠胚胎中表达，这是发育滞育期间所必需的。 Hesx1的缺失导致外胚层和原始内胚层决定簇的表达减少，并且滞育胚胎在植入后无法恢复胚胎发育。 Hesx1的基因缺失会降低多能性因子的表达并降低 LIF/STAT3 信号传导的活性，从而损害自我更新并促进向外胚层的分化。我们发现， Hesx1缺陷的 ESC 显示 ERK 通路激活升高，导致向原始内胚层加速分化，这可以通过Hesx1的过度表达来阻止。总之，我们的数据为Hesx1在控制 ESC 和小鼠胚胎的自我更新和维持未分化状态中的新作用提供了证据。