Disruption of fetal growth results in severe consequences to human health, including increased fetal and neonatal morbidity and mortality, as well as potential lifelong health problems. Molecular mechanisms promoting fetal growth represent potential therapeutic strategies to treat and/or prevent fetal growth restriction (FGR). Here, we identify a previously unknown role for the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) in promoting fetal and placental growth. We demonstrate that inactivation of MAP3K4 kinase activity causes FGR due in part to placental insufficiency. Significantly, MAP3K4 kinase–inactive mice display highly penetrant lethality prior to weaning and persistent growth reduction of surviving adults. Additionally, we elucidate molecular mechanisms by which MAP3K4 promotes growth through control of the insulin-like growth factor 1 receptor (IGF1R), insulin receptor (IR), and Akt signaling pathway. Specifically, MAP3K4 kinase inactivation in trophoblast stem (TS) cells results in reduced IGF1R and IR expression and decreased Akt activation. We observe these changes in TS cells also occur in differentiated trophoblasts created through in vitro differentiation of cultured TS cells and in vivo in placental tissues formed by TS cells. Furthermore, we show that MAP3K4 controls this pathway by promoting Igf1r transcript expression in TS cells through activation of CREB-binding protein (CBP). In the MAP3K4 kinase–inactive TS cells, Igf1r transcripts are repressed because of reduced CBP activity and increased histone deacetylase 6 expression and activity. Together, these data demonstrate a critical role for MAP3K4 in promoting fetal and placental growth by controlling the activity of the IGF1R/IR and Akt signaling pathway.

胎儿生长受阻会对人类健康造成严重后果，包括增加胎儿和新生儿的发病率和死亡率，以及潜在的终身健康问题。促进胎儿生长的分子机制代表了治疗和/或预防胎儿生长受限 (FGR) 的潜在治疗策略。在这里，我们确定了丝裂原活化蛋白激酶激酶 4 (MAP3K4) 在促进胎儿和胎盘生长中的未知作用。我们证明 MAP3K4 激酶活性的失活导致 FGR 部分是由于胎盘功能不全。值得注意的是，MAP3K4 激酶失活的小鼠在断奶前表现出高度外显性杀伤力，并且存活成虫的持续生长减少。此外，我们阐明了 MAP3K4 通过控制胰岛素样生长因子 1 受体 (IGF1R)、胰岛素受体 (IR) 和 Akt 信号通路促进生长的分子机制。具体而言，滋养层干 (TS) 细胞中的 MAP3K4 激酶失活导致 IGF1R 和 IR 表达降低，Akt 活化降低。我们观察到 TS 细胞的这些变化也发生在通过培养的 TS 细胞的体外分化和 TS 细胞形成的胎盘组织的体内分化。此外，我们表明 MAP3K4通过激活 CREB ​​结合蛋白 (CBP) 促进 TS 细胞中Igf1r转录物的表达来控制该途径。在 MAP3K4 激酶失活的 TS 细胞中，由于 CBP 活性降低和组蛋白去乙酰化酶 6 表达和活性增加， Igf1r转录物受到抑制。总之，这些数据证明了 MAP3K4 通过控制 IGF1R/IR 和 Akt 信号通路的活性在促进胎儿和胎盘生长中的关键作用。