Contribution of Maternal NODAL to Term Pregnancy

Term birth is a complex and wonderful process. Luckily, in most women the outcome is a full-term, healthy baby. However, preterm birth (,37 wk) is a major complication of pregnancy and is one of the leading causes of infant morbidity and mortality. Recent reports indicate that more than 12% of babies (approximately half a million annually) born in the United States are premature, and the rate of preterm birth has increased by nearly 35% since the early 1990s [1–3]. Premature babies that survive birth often suffer from developmental consequences that lead to increased risk of long-term disabilities [4, 5]. Numerous factors, including oxidative stress, infection and inflammation, genetics, cervical aberration, and progesterone resistance, are known to cause preterm birth [3, 6–8]. However, our current knowledge regarding this defect in pregnancy remains ill defined. Even with advances in medicine and technology, the gradual rise in preterm birth not only creates more disease-burdened lives but also presents long-lasting social and economic burdens. Therefore, there is an urgent need for basic research that uses various preclinical models to mechanistically approach this major health problem. In this regard, an interesting study published in the current issue of Biology of Reproduction by Park et al. [9] provides novel insights into the role of maternal NODAL in directing term birth in mouse pregnancy. NODAL, a secreted growth factor of the transforming growth factor beta family, plays a major role in embryonic growth regulation and anterior-posterior axis specification during embryogenesis. Its global deletion causes embryonic lethality by Day 10.5 of pregnancy in mice, primarily due to abnormal mesoderm development and hyperplasia of embryonic and extraembryonic ectoderm formation. In addition to NODAL’s involvement in embryonic development, previous studies by the same group had shown that NODAL exhibits a dynamic spatiotemporal expression pattern in the mouse uterus [10]. More specifically, glandular epithelial expression of NODAL throughout the preimplantation uterus becomes restricted to the interimplantation region following the onset of implantation on Days 4.5–6.5 of pregnancy (Day 0.5 1⁄4 vaginal plug). However, on Days 8.5–9.5, expression is more regionally distributed at the site of implantation in undifferentiated stroma surrounding the antimesometrial decidual bed, and is then ultimately shifted to a thin layer of decidua parietalis in the mesometrial decidual bed on Days 10.5–14.5. Overall, these results suggest that uterine NODAL plays a role in supporting appropriate decidualization. In addition, because NODAL is known to diffuse and act as a morphogen, it has been suggested by these researchers that NODAL expression in decidua parietalis may also help to support the appropriate development of extraembryonic tissues at the site of implantation during placentation. In continuation of previous studies, the present report [9] elegantly shows that conditional deletion of maternal Nodal under the direction of progesterone receptor-driven Cre promotes preterm birth and fetal death, primarily due to disruption at the site of the maternal-fetal connection during placentation (Fig. 1). Although histological and molecular marker studies show that early implantation-dependent decidualization is essentially normal on Day 8.5, the status of the decidua basalis layer appears to be dramatically disrupted during placental development on Day 12.5 in Nodal null mice, compared with the same region in control mice. Further studies indicate that the resulting defect contributes to significant fetal growth restriction rather than developmental anomalies on Days 15.5–16.5, prior to the onset of preterm birth on Day 17.5. Additional studies also show that the loss of the decidua basalis is primarily due to a lack of cell proliferation and increased apoptosis. Prostaglandins (PGs), such as PGE2 and PGF2a, derived from the maternal-fetal interface participate as contractile mediators to initiate parturition in many species [11]. The cyclooxygenase (Cox) enzymes, Cox-1 (official symbol PTGS1) and Cox-2 (official symbol PTGS2), can both convert arachidonic acid to PGH2, which is then converted to PGF2a, PGE2, and PGI2 by different PG synthases. The resulting PGF2a is particularly critical for the onset of ovarian luteolysis and the subsequent drop in serum progesterone levels prior to parturition in mice [12]. The onset of preterm labor in Nodal null mice appears to be coordinated with the upregulation of maternal PTGS2 and downregulation of progesterone on Day 16.5. Overall, the studies conducted thus far in the field provide convincing evidence to demonstrate that maternal NODAL controls proper development of the placenta, intrauterine fetal growth, and term delivery of healthy offspring. Although NODAL-driven complex molecular processes establishing the maternal-fetal connection remain unclear, it is interesting to note that a similar phenotype was also recently observed with the uterine deletion of Trp53 in mice [13]; the loss of TRP53 induces decidual senescence and loss of fetuses with preterm labor. Further studies found that the decidual senescence in Trp53 null mice is associated with increased signaling of mTORC1, a significant contributor to preterm Correspondence: Sanjoy K. Das, Division of Reproductive Sciences, S11.236, Cincinnati Children’s Hospital Medical Center, MLC 7045, 3333 Burnet Ave., Cincinnati, OH 45229. E-mail: sanjoy.das@cchmc.org