Division of Experimental Medicine, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Biol Reprod. 2012 Jun 28;86(6):194. doi: 10.1095/biolreprod.111.098277. Print 2012 Jun.
Preterm birth is the single leading cause of perinatal mortality in developed countries, affecting approximately 12% of pregnancies and accounting for 75% of neonatal loss in the United States. Despite the prevalence and severity of premature delivery, the causes and mechanisms that underlie spontaneous and idiopathic preterm birth remain unknown. Our inability to elucidate these fundamental causes has been attributed to a poor understanding of the signaling pathways associated with the premature induction of parturition and a lack of suitable animal models available for preterm birth research. In this study, we describe the generation and analysis of a novel conditional knockout of the transforming growth factor beta (TGFB) superfamily member, Nodal, from the maternal reproductive tract of mice. Strikingly, uterine Nodal knockout females exhibited a severe malformation of the maternal decidua basalis during placentation, leading to significant intrauterine growth restriction, and ultimately preterm birth and fetal loss on Day 17.5 of gestation. Using several approaches, we characterized aberrant placental development and demonstrated that reduced proliferation combined with increased apoptosis resulted in a diminished decidua basalis and compromised maternal-fetal interface. Last, we evaluated various components of the established parturition cascade and determined that preterm birth derived from the maternal Nodal knockout occurs prior to PTGS2 (COX-2) upregulation at the placental interface. Taken together, the results presented in this study highlight an in vivo role for maternal NODAL during placentation, present an interesting link between disrupted decidua basalis formation and premature parturition, and describe a potentially valuable model toward elucidating the complex processes that underlie preterm birth.
早产是发达国家围产期死亡的主要原因，影响约 12%的妊娠，占美国新生儿损失的 75%。尽管早产的普遍性和严重性很高，但自发性和特发性早产的原因和机制仍不清楚。我们无法阐明这些根本原因，这归因于我们对与分娩过早诱导相关的信号通路的理解不足，以及缺乏适用于早产研究的合适动物模型。在这项研究中，我们描述了从小鼠的母体生殖道中生成和分析转化生长因子β（TGFB）超家族成员 Nodal 的新型条件敲除。引人注目的是，子宫 Nodal 敲除的雌性在胎盘形成过程中表现出母体蜕膜基底的严重畸形，导致显著的宫内生长受限，最终在妊娠第 17.5 天早产和胎儿丢失。通过几种方法，我们对异常胎盘发育进行了特征描述，并证明增殖减少和凋亡增加导致蜕膜基底减少和母体-胎儿界面受损。最后，我们评估了已建立的分娩级联的各种成分，并确定源自母体 Nodal 敲除的早产发生在胎盘界面 PTGS2（COX-2）上调之前。总之，本研究中的结果强调了母体 NODAL 在胎盘形成过程中的体内作用，提出了蜕膜基底形成中断与早产之间的有趣联系，并描述了一个有价值的模型，用于阐明导致早产的复杂过程。
