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An essential role for maternal control of Nodal signaling.

ABSTRACT: Growth factor signaling is essential for pattern formation, growth, differentiation, and maintenance of stem cell pluripotency. Nodal-related signaling factors are required for axis formation and germ layer specification from sea urchins to mammals. Maternal transcripts of the zebrafish Nodal factor, Squint (Sqt), are localized to future embryonic dorsal. The mechanisms by which maternal sqt/nodal RNA is localized and regulated have been unclear. Here, we show that maternal control of Nodal signaling via the conserved Y box-binding protein 1 (Ybx1) is essential. We identified Ybx1 via a proteomic screen. Ybx1 recognizes the 3' untranslated region (UTR) of sqt RNA and prevents premature translation and Sqt/Nodal signaling. Maternal-effect mutations in zebrafish ybx1 lead to deregulated Nodal signaling, gastrulation failure, and embryonic lethality. Implanted Nodal-coated beads phenocopy ybx1 mutant defects. Thus, Ybx1 prevents ectopic Nodal activity, revealing a new paradigm in the regulation of Nodal signaling, which is likely to be conserved. DOI:http://dx.doi.org/10.7554/eLife.00683.001.

SUBMITTER: Kumari P

PROVIDER: S-EPMC3771576 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An essential role for maternal control of Nodal signaling.

Kumari Pooja P Gilligan Patrick C PC Lim Shimin S Tran Long Duc LD Winkler Sylke S Philp Robin R Sampath Karuna K

eLife 20130910

Growth factor signaling is essential for pattern formation, growth, differentiation, and maintenance of stem cell pluripotency. Nodal-related signaling factors are required for axis formation and germ layer specification from sea urchins to mammals. Maternal transcripts of the zebrafish Nodal factor, Squint (Sqt), are localized to future embryonic dorsal. The mechanisms by which maternal sqt/nodal RNA is localized and regulated have been unclear. Here, we show that maternal control of Nodal sign ...[more]

PMID: 24040511

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Project description:Nodal, a secreted signaling protein from the transforming growth factor beta (TGF-?)-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-?/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.

Project description:Aerobic exercise training improves the autonomic control of the circulation. Emerging evidence has shown that exercise induces neuroplastic adaptive changes in preautonomic circuitry controlling sympathetic/parasympathetic outflow to heart and vessels. The mechanisms underlying neuronal plasticity are, however, incompletely understood. Knowing that sinoaortic denervation blocks training-induced cardiovascular benefits, we investigate whether baroreceptors' and chemoreceptors' signaling are able to drive neuronal plasticity within medullary and supramedullary pathways controlling autonomic outflow. Male Wistar rats submitted to sinoaortic denervation (SAD) or dopamine β-hydroxylase-saporin lesion (DBHx) and respective controls (SHAM) were allocated to training (T) or sedentary (S) protocols for 8 weeks. After hemodynamic measurements at rest, rats were deeply anesthetized for brain harvesting. The density of DBH and oxytocin (OT) cell bodies and terminals were analyzed in brainstem and hypothalamic brain areas (double immunofluorescence reactions, optic and confocal microscopy). In SHAM rats training augmented the density of DBH+ neurons in the nucleus of solitary tract, increased the density of ascending NORergic projections and the number of DBH+ boutons contacting preautonomic OT+ neurons into paraventricular hypothalamic preautonomic nuclei, augmented the density of local OTergic neurons and enhanced the density of OT+ terminals targeting brainstem autonomic areas. These plastic changes occurred simultaneously with reduced sympathetic/increased parasympathetic activity, augmented baroreflex sensitivity and reduced resting heart rate. SAD reduced the density of both DBH+ fibers ascending from brainstem to paraventricular nucleus of hypothalamus and preautonomic OT+ neurons projecting to the brainstem, abrogated training-induced plastic changes and autonomic adaptive responses without changing the treadmill performance. Minor neuroplastic changes with preserved baroreflex sensitivity were observed in trained rats after partial selective disruption of ascending NORergic projections. Our data indicated that afferent inputs conveyed by arterial baroreceptors and chemoreceptors are the main stimuli to drive both inactivity-induced and activity-dependent neuroplasticity within the autonomic circuitry.

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An essential role for maternal control of Nodal signaling.

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An essential role for maternal control of Nodal signaling.

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