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CURATOR
A pinboard by
Lisa Starr

Postdoctoral Fellw, Research Institute of the McGill University Health Centre

PINBOARD SUMMARY

Nodal regulates uterine immune cells that control the timing of birth

Millions of babies are born prematurely every year but the cause of most of these preterm births is unknown. Part of the reason is that we do not fully understand what determines when a baby is born. Our lab is investigating if a molecule called Nodal, which is present in the uterus during pregnancy, is involved in the timing of birth. When we delete the Nodal gene in mice 80% give birth prematurely, 2 days earlier than the usual 19 days of gestation. These mice also have more immune cells in their uteri, like macrophages and natural killer cells, than in regular mice. This could explain their preterm birth because immune cells are involved in initiating birth. Nodal may be a molecule that ensures that these cells are present and active only at the appropriate time. After examining Nodal in mice, we wanted to see if its role is similar in humans. We sequenced the Nodal gene of pregnant women to see if women with mutations were more likely to give birth early. We discovered an interaction between Nodal mutation and infection. Nodal mutations increased the risk of preterm in birth in women without an infection. But women who had a placental infection as well as a Nodal mutation were actually less likely to give birth early. It is possible that Nodal mutations increase the number of immune cells in the uterus. This could be beneficial in women with an infection, as infection is a leading cause of preterm birth. On the other hand, without an infection present, immune cells might signal for birth to happen too soon. We hope that our findings will help to identify women that are at risk for giving birth early and develop treatments to prevent preterm birth.

10 ITEMS PINNED

Long-term medical and social consequences of preterm birth.

Abstract: Advances in perinatal care have increased the number of premature babies who survive. There are concerns, however, about the ability of these children to cope with the demands of adulthood.We linked compulsory national registries in Norway to identify children of different gestational-age categories who were born between 1967 and 1983 and to follow them through 2003 in order to document medical disabilities and outcomes reflecting social performance.The study included 903,402 infants who were born alive and without congenital anomalies (1822 born at 23 to 27 weeks of gestation, 2805 at 28 to 30 weeks, 7424 at 31 to 33 weeks, 32,945 at 34 to 36 weeks, and 858,406 at 37 weeks or later). The proportions of infants who survived and were followed to adult life were 17.8%, 57.3%, 85.7%, 94.6%, and 96.5%, respectively. Among the survivors, the prevalence of having cerebral palsy was 0.1% for those born at term versus 9.1% for those born at 23 to 27 weeks of gestation (relative risk for birth at 23 to 27 weeks of gestation, 78.9; 95% confidence interval [CI], 56.5 to 110.0); the prevalence of having mental retardation, 0.4% versus 4.4% (relative risk, 10.3; 95% CI, 6.2 to 17.2); and the prevalence of receiving a disability pension, 1.7% versus 10.6% (relative risk, 7.5; 95% CI, 5.5 to 10.0). Among those who did not have medical disabilities, the gestational age at birth was associated with the education level attained, income, receipt of Social Security benefits, and the establishment of a family, but not with rates of unemployment or criminal activity.In this cohort of people in Norway who were born between 1967 and 1983, the risks of medical and social disabilities in adulthood increased with decreasing gestational age at birth.

Pub.: 19 Jul '08, Pinned: 30 Jun '17

Maternal Nodal inversely affects NODAL and STOX1 expression in the fetal placenta.

Abstract: Nodal, a secreted signaling protein from the transforming growth factor beta (TGF-β)-super family plays a vital role during early embryonic development. Recently, it was found that maternal decidua-specific Nodal knockout mice show intrauterine growth restriction (IUGR) and preterm birth. The chromosomal location of NODAL is in the same linkage area as the placental (fetal) pre-eclampsia (PE) susceptibility gene STOX1, which is associated with the familial form of early-onset, IUGR-complicated PE. As the STOX1 linkage was originally identified in women being born from a pre-eclamptic pregnancy as well as suffering from PE themselves, the linkage could in part be caused by NODAL, which is why the potential maternal-fetal interaction between STOX1 and NODAL was investigated. In the PE families with the STOX1 susceptibility allele carried by the children born from pre-eclamptic pregnancies, it was found that the pre-eclamptic mothers themselves all carried the NODAL H165R SNP, which causes a 50% reduced activity. Surprisingly, in decidua-specific Nodal knockout mice the fetal placenta showed up-regulation of STOX1 and NODAL expression. Conditioned media of human first trimester decidua and a human endometrial stromal cell line (T-HESC) treated with siRNAs against NODAL or carrying the H165R SNP were also able to induce NODAL and STOX1 expression when added to SGHPL-5 first trimester extravillous trophoblast cells. Finally, a human TGF-β/BMP signaling pathway PCR-array on decidua and the T-HESC cell line with Nodal knockdown revealed upregulation of Activin-A, which was confirmed in conditioned media by ELISA. We show that maternal decidua Nodal knockdown gives upregulation of NODAL and STOX1 mRNA expression in fetal extravillous trophoblast cells, potentially via upregulation of Activin-A in the maternal decidua. As both Activin-A and Nodal have been implicated in PE, being increased in serum of pre-eclamptic women and upregulated in pre-eclamptic placentas respectively, this interaction at the maternal-fetal interface might play a substantial role in the development of PE.

Pub.: 30 Aug '13, Pinned: 30 Jun '17

NODAL in the uterus is necessary for proper placental development and maintenance of pregnancy.

Abstract: 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.

Pub.: 02 Mar '12, Pinned: 30 Jun '17

Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling.

Abstract: Cripto-1 is an oncogenic protein belonging to the epidermal growth factor-Cripto-1/FRL-1/Cryptic family. It has important roles in tumor formation and metastasis, but its effects on the immune system are unclear. In the present study, we investigated the effects of Cripto-1 overexpression on macrophage activities and examined the underlying mechanisms. A cell line stably overexpressing Cripto-1 was developed. The culture supernatant from this cell line was collected and used to condition macrophages (RAW264.7, THP-1, and primary mouse macrophages) for various times. Exposure to this supernatant significantly increased the mRNA and protein expression levels of the anti-inflammatory cytokine interleukin (IL)-10 and of three pro-inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β), but did not affect the expression of transforming growth factor-β, another anti-inflammatory cytokine. Exposure to this supernatant also enhanced macrophage phagocytosis of chicken erythrocytes and yeast cells. Similar effects were observed in macrophages stimulated with purified Cripto-1 protein. Mechanistic experiments revealed that Cripto-1 activated nuclear factor (NF)-κB signaling by inducing IκB kinase phosphorylation and p65 nuclear translocation. Pretreatment with ammonium pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, inhibited Cripto-1-induced cytokine secretion and phagocytosis of macrophages. Taken together, our present findings suggest that Cripto-1 enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-κB signaling pathway.

Pub.: 20 Oct '15, Pinned: 30 Jun '17