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

Thulluru HK, Park C, Dufort D, Kleiverda G, Oudejans C, van Dijk M - Front Genet (2013)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Chemistry, Vrije Universiteit Medical Center Amsterdam, Netherlands ; Institute for Cardiovascular Research, Vrije Universiteit Medical Center Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

NODAL and STOX1 expression in SGHPL-5 cells after addition of decidual tissue conditioned media.NODAL(A) and STOX1(B) mRNA expression in SGHPL-5 cells treated with decidua conditioned media from gestational age-matched week 6 (n = 4) and week 8–9 (n = 4) decidua tissues carrying Nodal H165R (n = 2 per gestational age) relative to wildtype (WT; n = 2 per gestational age) alleles. (C)NODAL and STOX1 mRNA expression in SGHPL-5 cells treated with decidua conditioned media from deciduas treated with Nodal siRNAs relative to scrambled control (n = 4). *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3753557&req=5

Figure 3: NODAL and STOX1 expression in SGHPL-5 cells after addition of decidual tissue conditioned media.NODAL(A) and STOX1(B) mRNA expression in SGHPL-5 cells treated with decidua conditioned media from gestational age-matched week 6 (n = 4) and week 8–9 (n = 4) decidua tissues carrying Nodal H165R (n = 2 per gestational age) relative to wildtype (WT; n = 2 per gestational age) alleles. (C)NODAL and STOX1 mRNA expression in SGHPL-5 cells treated with decidua conditioned media from deciduas treated with Nodal siRNAs relative to scrambled control (n = 4). *P < 0.05.

Mentions: We tested if the effects of decidual Nodal knockdown on placental expression as found in mice could also be seen in the human placenta. For this, we collected first trimester decidual tissues carrying either wildtype or NODAL H165R SNP alleles. Conditioned media from these gestational age-matched decidual tissues (week 6 and week 8–9) were added to SGHPL-5 cells, a first trimester extravillous trophoblast cell line. These cells subsequently showed upregulation of both NODAL and STOX1 expression when the conditioned media was from decidual tissue carrying the H165R SNP alleles (Figures 3A,B). In this small number of decidua tissues (n = 2 in each group), statistical significance was reached for STOX1 expression showing upregulation at a gestational age of 6 weeks, while the observed upregulated STOX1 expression at gestational age 8–9 weeks and upregulated NODAL expression at both gestational age timepoints did not reach statistical significance. SGHPL-5 cells incubated with conditioned media of decidual tissues (week 8–9) treated with siRNAs against Nodal or scrambled controls showed significant upregulation of NODAL, while the upregulated STOX1 expression observed did not reach statistical significance(Figure 3C).


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

Thulluru HK, Park C, Dufort D, Kleiverda G, Oudejans C, van Dijk M - Front Genet (2013)

NODAL and STOX1 expression in SGHPL-5 cells after addition of decidual tissue conditioned media.NODAL(A) and STOX1(B) mRNA expression in SGHPL-5 cells treated with decidua conditioned media from gestational age-matched week 6 (n = 4) and week 8–9 (n = 4) decidua tissues carrying Nodal H165R (n = 2 per gestational age) relative to wildtype (WT; n = 2 per gestational age) alleles. (C)NODAL and STOX1 mRNA expression in SGHPL-5 cells treated with decidua conditioned media from deciduas treated with Nodal siRNAs relative to scrambled control (n = 4). *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753557&req=5

Figure 3: NODAL and STOX1 expression in SGHPL-5 cells after addition of decidual tissue conditioned media.NODAL(A) and STOX1(B) mRNA expression in SGHPL-5 cells treated with decidua conditioned media from gestational age-matched week 6 (n = 4) and week 8–9 (n = 4) decidua tissues carrying Nodal H165R (n = 2 per gestational age) relative to wildtype (WT; n = 2 per gestational age) alleles. (C)NODAL and STOX1 mRNA expression in SGHPL-5 cells treated with decidua conditioned media from deciduas treated with Nodal siRNAs relative to scrambled control (n = 4). *P < 0.05.
Mentions: We tested if the effects of decidual Nodal knockdown on placental expression as found in mice could also be seen in the human placenta. For this, we collected first trimester decidual tissues carrying either wildtype or NODAL H165R SNP alleles. Conditioned media from these gestational age-matched decidual tissues (week 6 and week 8–9) were added to SGHPL-5 cells, a first trimester extravillous trophoblast cell line. These cells subsequently showed upregulation of both NODAL and STOX1 expression when the conditioned media was from decidual tissue carrying the H165R SNP alleles (Figures 3A,B). In this small number of decidua tissues (n = 2 in each group), statistical significance was reached for STOX1 expression showing upregulation at a gestational age of 6 weeks, while the observed upregulated STOX1 expression at gestational age 8–9 weeks and upregulated NODAL expression at both gestational age timepoints did not reach statistical significance. SGHPL-5 cells incubated with conditioned media of decidual tissues (week 8–9) treated with siRNAs against Nodal or scrambled controls showed significant upregulation of NODAL, while the upregulated STOX1 expression observed did not reach statistical significance(Figure 3C).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Chemistry, Vrije Universiteit Medical Center Amsterdam, Netherlands ; Institute for Cardiovascular Research, Vrije Universiteit Medical Center Amsterdam, Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus