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Alexander F. Schier - One of the best experts on this subject based on the ideXlab platform.

  • toddler Signaling regulates mesodermal cell migration downstream of Nodal Signaling
    eLife, 2017
    Co-Authors: Megan L Norris, Andrea Pauli, James A Gagnon, Nathan D Lord, Katherine W Rogers, Christian Mosimann, Leonard I Zon, Alexander F. Schier
    Abstract:

    Toddler/Apela/Elabela is a conserved secreted peptide that regulates mesendoderm development during zebrafish gastrulation. Two non-exclusive models have been proposed to explain Toddler function. The 'specification model' postulates that Toddler Signaling enhances Nodal Signaling to properly specify endoderm, whereas the 'migration model' posits that Toddler Signaling regulates mesendodermal cell migration downstream of Nodal Signaling. Here, we test key predictions of both models. We find that in toddler mutants Nodal Signaling is initially normal and increasing endoderm specification does not rescue mesendodermal cell migration. Mesodermal cell migration defects in toddler mutants result from a decrease in animal pole-directed migration and are independent of endoderm. Conversely, endodermal cell migration defects are dependent on a Cxcr4a-regulated tether of the endoderm to mesoderm. These results suggest that Toddler Signaling regulates mesodermal cell migration downstream of Nodal Signaling and indirectly affects endodermal cell migration via Cxcr4a-Signaling.

  • Nodal Signaling promotes the speed and directional movement of cardiomyocytes in zebrafish
    Developmental dynamics : an official publication of the American Association of Anatomists, 2008
    Co-Authors: Maria Ines Medeiros De Campos-baptista, Nathalia G. Holtzman, Deborah Yelon, Alexander F. Schier
    Abstract:

    Members of the Nodal family regulate left-right asymmetry during vertebrate organogenesis, but it is unclear how Nodal Signaling controls asymmetric morphogenesis at the cellular level. We used high-resolution time-lapse imaging in zebrafish to compare the movements of cardiomyocytes in the presence or absence of Nodal Signaling. Loss of Nodal Signaling in late-zygotic mutants for the Nodal co-receptor one-eyed pinhead (LZoep) abolished the leftward movement of cardiomyocytes. Global heart rotation was blocked but cardiomyocyte neighbor relationships were maintained as in wild type. Cardiomyocytes in LZoep mutants moved more slowly and less directionally than their wild-type counterparts. The phenotypes observed in the absence of Nodal Signaling strongly resemble abnormalities found in BMP Signaling mutants. These results indicate that a Nodal-BMP Signaling cascade drives left-right heart morphogenesis by regulating the speed and direction of cardiomyocyte movement. Developmental Dynamics 237:3624–3633, 2008. © 2008 Wiley-Liss, Inc.

  • Nodal Signaling activates differentiation genes during zebrafish gastrulation
    Developmental biology, 2007
    Co-Authors: James T. Bennett, Katherine Joubin, Simon Cheng, Pia Aanstad, Ralf Herwig, Matthew D. Clark, Hans Lehrach, Alexander F. Schier
    Abstract:

    Nodal signals induce mesodermal and endodermal progenitors during vertebrate development. To determine the role of Nodal Signaling at a genomic level, we isolated Nodal-regulated genes by expression profiling using macroarrays and gene expression databases. Putative Nodal-regulated genes were validated by in situ hybridization screening in wild type and Nodal Signaling mutants. 46 genes were identified, raising the currently known number of Nodal-regulated genes to 72. Based on their expression patterns along the dorsoventral axis, most of these genes can be classified into two groups. One group is expressed in the dorsal margin, whereas the other group is expressed throughout the margin. In addition to transcription factors and Signaling components, the screens identified several new functional classes of Nodal-regulated genes, including cytoskeletal components and molecules involved in protein secretion or endoplasmic reticulum stress. We found that x-box binding protein-1 (xbp1) is a direct target of Nodal Signaling and required for the terminal differentiation of the hatching gland, a specialized secretory organ whose specification is also dependent on Nodal Signaling. These results indicate that Nodal Signaling regulates not only specification genes but also differentiation genes.

  • mixer bon and foxh1 sur have overlapping and divergent roles in Nodal Signaling and mesendoderm induction
    Development, 2003
    Co-Authors: Prabhat S. Kunwar, Malcolm Whitman, James T. Bennett, Steven Zimmerman, Yu Chen, Alexander F. Schier
    Abstract:

    Transcription factors belonging to the FoxH1 and Mixer families are required for facets of Nodal Signaling during vertebrate mesendoderm induction. Here, we analyze whether zebrafish proteins related to FoxH1 [Schmalspur (Sur)] and Mixer [Bonnie and clyde (Bon)] act within or downstream of the Nodal Signaling pathway, test whether these two factors have additive or overlapping activities, and determine whether FoxH1/Sur and Mixer/Bon can account for all Nodal Signaling during embryogenesis. We find that sur expression is independent of Nodal Signaling and that bon is expressed in the absence of Nodal Signaling but requires Nodal Signaling and Sur for enhanced, maintained expression. These results and the association of FoxH1 and Mixer/Bon with phosphorylated Smad2 support a role for these factors as components of the Nodal Signaling pathway. In contrast to the relatively mild defects observed in single mutants, loss of both bon and sur results in a severe phenotype characterized by absence of prechordal plate, cardiac mesoderm, endoderm and ventral neuroectoderm. Analysis of Nodal-regulated proteins reveals that Bon and Sur have both distinct and overlapping regulatory roles. Some genes are regulated by both Bon and Sur, and others by either Bon or Sur. Complete loss of Nodal Signaling results in a more severe phenotype than loss of both Bon and Sur, indicating that additional Smad-associated transcription factors remain to be identified that act as components of the Nodal Signaling pathway.

  • Mixer/Bon and FoxH1/Sur have overlapping and divergent roles in Nodal Signaling and mesendoderm induction.
    Development (Cambridge England), 2003
    Co-Authors: Prabhat S. Kunwar, Malcolm Whitman, James T. Bennett, Steven Zimmerman, Yu Chen, Alexander F. Schier
    Abstract:

    Transcription factors belonging to the FoxH1 and Mixer families are required for facets of Nodal Signaling during vertebrate mesendoderm induction. Here, we analyze whether zebrafish proteins related to FoxH1 [Schmalspur (Sur)] and Mixer [Bonnie and clyde (Bon)] act within or downstream of the Nodal Signaling pathway, test whether these two factors have additive or overlapping activities, and determine whether FoxH1/Sur and Mixer/Bon can account for all Nodal Signaling during embryogenesis. We find that sur expression is independent of Nodal Signaling and that bon is expressed in the absence of Nodal Signaling but requires Nodal Signaling and Sur for enhanced, maintained expression. These results and the association of FoxH1 and Mixer/Bon with phosphorylated Smad2 support a role for these factors as components of the Nodal Signaling pathway. In contrast to the relatively mild defects observed in single mutants, loss of both bon and sur results in a severe phenotype characterized by absence of prechordal plate, cardiac mesoderm, endoderm and ventral neuroectoderm. Analysis of Nodal-regulated proteins reveals that Bon and Sur have both distinct and overlapping regulatory roles. Some genes are regulated by both Bon and Sur, and others by either Bon or Sur. Complete loss of Nodal Signaling results in a more severe phenotype than loss of both Bon and Sur, indicating that additional Smad-associated transcription factors remain to be identified that act as components of the Nodal Signaling pathway.

Roger A. Pedersen - One of the best experts on this subject based on the ideXlab platform.

  • activin Nodal Signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors
    Stem Cells, 2011
    Co-Authors: Stephanie Brown, Adrian Kee Keong Teo, Matthew Trotter, Candy H.-h. Cho, Siim Pauklin, Nicholas R F Hannan, Bing Lim, Leah A Vardy, Ray N Dunn, Roger A. Pedersen
    Abstract:

    Activin/Nodal Signaling is necessary to maintain pluripotency of human embryonic stem cells (hESCs) and to induce their differentiation toward endoderm. However, the mechanisms by which Activin/Nodal Signaling achieves these opposite functions remain unclear. To unravel these mechanisms, we examined the transcriptional network controlled in hESCs by Smad2 and Smad3, which represent the direct effectors of Activin/Nodal Signaling. These analyses reveal that Smad2/3 participate in the control of the core transcriptional network characterizing pluripotency, which includes Oct-4, Nanog, FoxD3, Dppa4, Tert, Myc, and UTF1. In addition, similar experiments performed on endoderm cells confirm that a broad part of the transcriptional network directing differentiation is downstream of Smad2/3. Therefore, Activin/Nodal Signaling appears to control divergent transcriptional networks in hESCs and in endoderm. Importantly, we observed an overlap between the transcriptional network downstream of Nanog and Smad2/3 in hESCs; whereas, functional studies showed that both factors cooperate to control the expression of pluripotency genes. Therefore, the effect of Activin/Nodal Signaling on pluripotency and differentiation could be dictated by tissue specific Smad2/3 partners such as Nanog, explaining the mechanisms by which Signaling pathways can orchestrate divergent cell fate decisions. STEM CELLS 2011;29:1176–1185

  • Activin/Nodal Signaling controls divergent transcriptional networks in human embryonic stem cells and in endoderm progenitors.
    Stem cells (Dayton Ohio), 2011
    Co-Authors: Stephanie Brown, Adrian Kee Keong Teo, Matthew Trotter, Candy H.-h. Cho, Siim Pauklin, Nicholas R F Hannan, Bing Lim, Leah A Vardy, Ray N Dunn, Roger A. Pedersen
    Abstract:

    Activin/Nodal Signaling is necessary to maintain pluripotency of human embryonic stem cells (hESCs) and to induce their differentiation toward endoderm. However, the mechanisms by which Activin/Nodal Signaling achieves these opposite functions remain unclear. To unravel these mechanisms, we examined the transcriptional network controlled in hESCs by Smad2 and Smad3, which represent the direct effectors of Activin/Nodal Signaling. These analyses reveal that Smad2/3 participate in the control of the core transcriptional network characterizing pluripotency, which includes Oct-4, Nanog, FoxD3, Dppa4, Tert, Myc, and UTF1. In addition, similar experiments performed on endoderm cells confirm that a broad part of the transcriptional network directing differentiation is downstream of Smad2/3. Therefore, Activin/Nodal Signaling appears to control divergent transcriptional networks in hESCs and in endoderm. Importantly, we observed an overlap between the transcriptional network downstream of Nanog and Smad2/3 in hESCs; whereas, functional studies showed that both factors cooperate to control the expression of pluripotency genes. Therefore, the effect of Activin/Nodal Signaling on pluripotency and differentiation could be dictated by tissue specific Smad2/3 partners such as Nanog, explaining the mechanisms by which Signaling pathways can orchestrate divergent cell fate decisions. STEM CELLS 2011;29:1176–1185

  • Activin/Nodal Signaling and Pluripotency
    Vitamins and hormones, 2011
    Co-Authors: Zhenzhi Chng, Ludovic Vallier, Roger A. Pedersen
    Abstract:

    Maintenance of a pluripotent cell population during mammalian embryogenesis is crucial for the proper generation of extraembryonic and embryonic tissues to ensure intrauterine survival and fetal development. Pluripotent stem cells derived from early stage mammalian embryos are known as “embryonic stem cells.” Such embryo-derived stem cells can proliferate indefinitely in vitro and give rise to derivatives of all three primary germ layers. Their potential for clinical and commercial applications has sparked great excitement within scientific and lay communities. Identification of the Signaling pathways controlling stem cell pluripotency and differentiation provides knowledge-based approaches to manipulate stem cells for regenerative medicine. One of the Signaling cascades that has been identified in the control of stem cell pluripotency and differentiation is the Activin/Nodal pathway. Here, we describe the differences among pluripotent cell types and discuss the latest findings on the molecular mechanisms involving Activin/Nodal Signaling in controlling their pluripotency and differentiation.

  • activin Nodal Signaling and pluripotency
    Vitamins and Hormones Series, 2011
    Co-Authors: Zhenzhi Chng, Ludovic Vallier, Roger A. Pedersen
    Abstract:

    Maintenance of a pluripotent cell population during mammalian embryogenesis is crucial for the proper generation of extraembryonic and embryonic tissues to ensure intrauterine survival and fetal development. Pluripotent stem cells derived from early stage mammalian embryos are known as "embryonic stem cells." Such embryo-derived stem cells can proliferate indefinitely in vitro and give rise to derivatives of all three primary germ layers. Their potential for clinical and commercial applications has sparked great excitement within scientific and lay communities. Identification of the Signaling pathways controlling stem cell pluripotency and differentiation provides knowledge-based approaches to manipulate stem cells for regenerative medicine. One of the Signaling cascades that has been identified in the control of stem cell pluripotency and differentiation is the Activin/Nodal pathway. Here, we describe the differences among pluripotent cell types and discuss the latest findings on the molecular mechanisms involving Activin/Nodal Signaling in controlling their pluripotency and differentiation.

  • inhibition of activin Nodal Signaling promotes specification of human embryonic stem cells into neuroectoderm
    Developmental Biology, 2008
    Co-Authors: Joseph R Smith, Ludovic Vallier, Giuseppe Lupo, Morgan Alexander, William A Harris, Roger A. Pedersen
    Abstract:

    Abstract Nodal, a member of the TGF-β family of Signaling molecules, has been implicated in pluripotency in human embryonic stem cells (hESCs) [Vallier, L., Reynolds, D., Pedersen, R.A., 2004a. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev. Biol. 275, 403–421], a finding that seems paradoxical given Nodal's central role in mesoderm/endoderm specification during gastrulation. In this study, we sought to clarify the role of Nodal Signaling during hESC differentiation by constitutive overexpression of the endogenous Nodal inhibitors Lefty2 (Lefty) and truncated Cerberus (Cerb-S) and by pharmacological interference using the Nodal receptor antagonist SB431542. Compared to wildtype (WT) controls, embryoid bodies (EBs) derived from either Lefty or Cerb-S overexpressing hESCs showed increased expression of neuroectoderm markers Sox1, Sox3, and Nestin. Conversely, they were negative for a definitive endoderm marker (Sox17) and did not generate beating cardiomyocyte structures in conditions that allowed mesendoderm differentiation from WT hESCs. EBs derived from either Lefty or Cerb-S expressing hESCs also contained a greater abundance of neural rosette structures as compared to controls. Differentiating EBs derived from Lefty expressing hESCs generated a dense network of β-tubulin III positive neurites, and when Lefty expressing hESCs were grown as a monolayer and allowed to differentiate, they generated significantly higher numbers of β-tubulin positive neurons as compared to wildtype hESCs. SB431542 treatments reproduced the neuralising effects of Lefty overexpression in hESCs. These results show that inhibition of Nodal Signaling promotes neuronal specification, indicating a role for this pathway in controlling early neural development of pluripotent cells.

Balaji M. Rao - One of the best experts on this subject based on the ideXlab platform.

  • activin Nodal Signaling switches the terminal fate of human embryonic stem cell derived trophoblasts
    Journal of Biological Chemistry, 2015
    Co-Authors: Prasenjit Sarkar, Shan M. Randall, Timothy S. Collier, Anthony Nero, Teal Russell, David C. Muddiman, Balaji M. Rao
    Abstract:

    Human embryonic stem cells (hESCs) have been routinely treated with bone morphogenetic protein and/or inhibitors of activin/Nodal Signaling to obtain cells that express trophoblast markers. Trophoblasts can terminally differentiate to either extravillous trophoblasts or syncytiotrophoblasts. The Signaling pathways that govern the terminal fate of these trophoblasts are not understood. We show that activin/Nodal Signaling switches the terminal fate of these hESC-derived trophoblasts. Inhibition of activin/Nodal Signaling leads to formation of extravillous trophoblast, whereas loss of activin/Nodal inhibition leads to the formation of syncytiotrophoblasts. Also, the ability of hESCs to form bona fide trophoblasts has been intensely debated. We have examined hESC-derived trophoblasts in the light of stringent criteria that were proposed recently, such as hypomethylation of the ELF5-2b promoter region and down-regulation of HLA class I antigens. We report that trophoblasts that possess these properties can indeed be obtained from hESCs.

  • Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts
    The Journal of biological chemistry, 2015
    Co-Authors: Prasenjit Sarkar, Shan M. Randall, Timothy S. Collier, Anthony Nero, Teal Russell, David C. Muddiman, Balaji M. Rao
    Abstract:

    Human embryonic stem cells (hESCs) have been routinely treated with bone morphogenetic protein and/or inhibitors of activin/Nodal Signaling to obtain cells that express trophoblast markers. Trophoblasts can terminally differentiate to either extravillous trophoblasts or syncytiotrophoblasts. The Signaling pathways that govern the terminal fate of these trophoblasts are not understood. We show that activin/Nodal Signaling switches the terminal fate of these hESC-derived trophoblasts. Inhibition of activin/Nodal Signaling leads to formation of extravillous trophoblast, whereas loss of activin/Nodal inhibition leads to the formation of syncytiotrophoblasts. Also, the ability of hESCs to form bona fide trophoblasts has been intensely debated. We have examined hESC-derived trophoblasts in the light of stringent criteria that were proposed recently, such as hypomethylation of the ELF5-2b promoter region and down-regulation of HLA class I antigens. We report that trophoblasts that possess these properties can indeed be obtained from hESCs.

Thierry Lepage - One of the best experts on this subject based on the ideXlab platform.

  • A conserved role for the Nodal Signaling pathway in the establishment of dorso-ventral and left-right axes in deuterostomes.
    Journal of experimental zoology. Part B Molecular and developmental evolution, 2008
    Co-Authors: Veronique Duboc, Thierry Lepage
    Abstract:

    Nodal factors play crucial roles during embryogenesis of chordates. They have been implicated in a number of developmental processes, including mesoderm and endoderm formation and patterning of the embryo along the anterior-posterior and left-right axes. We have analyzed the function of the Nodal Signaling pathway during the embryogenesis of the sea urchin, a non-chordate organism. We found that Nodal Signaling plays a central role in axis specification in the sea urchin, but surprisingly, its first main role appears to be in ectoderm patterning and not in specification of the endoderm and mesoderm germ layers as in vertebrates. Starting at the early blastula stage, sea urchin Nodal is expressed in the presumptive oral ectoderm where it controls the formation of the oral-aboral axis. A second conserved role for Nodal Signaling during vertebrate evolution is its involvement in the establishment of left-right asymmetries. Sea urchin larvae exhibit profound left-right asymmetry with the formation of the adult rudiment occurring only on the left side. We found that a Nodal/lefty/pitx2 gene cassette regulates left-right asymmetry in the sea urchin but that intriguingly, the expression of these genes is reversed compared to vertebrates. We have shown that Nodal signals emitted from the right ectoderm of the larva regulate the asymmetrical morphogenesis of the coelomic pouches by inhibiting rudiment formation on the right side of the larva. This result shows that the mechanisms responsible for patterning the left-right axis are conserved in echinoderms and that this role for Nodal is conserved among the deuterostomes. We will discuss the implications regarding the reference axes of the sea urchin and the ancestral function of the Nodal gene in the last section of this review.

  • left right asymmetry in the sea urchin embryo is regulated by Nodal Signaling on the right side
    Developmental Cell, 2005
    Co-Authors: Veronique Duboc, Lydia Besnardeau, Eric Röttinger, Francois Lapraz, Thierry Lepage
    Abstract:

    The asymmetric positioning of internal organs on the left or right side of the body is highly conserved in vertebrates and relies on a Nodal Signaling pathway acting on the left side of the embryo. Whether the same pathway also regulates left-right asymmetry in invertebrates and what is the evolutionary origin of the mechanisms controlling left-right determination are not known. Here, we show that Nodal regulates left-right asymmetry in the sea urchin but that, intriguingly, its expression is reversed compared to vertebrates. Nodal signals emitted from the right side of the larva prevent the right coelomic pouch from forming the imaginal rudiment. Inhibition of Nodal Signaling after gastrulation causes formation of an ectopic rudiment on the right side, leading to twinned urchins after metamorphosis. In contrast, ectopic activation of the pathway prevents formation of the rudiment. Our results show that the mechanisms responsible for left-right determination are conserved within basal deuterostomes.

  • The Pitx2 Homeobox Protein Is Required Early for Endoderm Formation and Nodal Signaling
    Developmental biology, 2001
    Co-Authors: Marion Faucourt, Evelyn Houliston, Lydia Besnardeau, David Kimelman, Thierry Lepage
    Abstract:

    Abstract Nodal and Nodal-related factors play fundamental roles in a number of developmental processes, including mesoderm and endoderm formation, patterning of the anterior neural plate, and determination of bilateral asymmetry in vertebrates. pitx2, a paired-like homeobox gene, has been proposed to act downstream of Nodal in the gene cascade providing left–right cues to the developing organs. Here, we report that pitx2 is required early in the Nodal Signaling pathway for specification of the endodermal and mesodermal germ layers. We found that pitx2 is expressed very early during Xenopus and zebrafish development and in many regions where Nodal Signaling is required, including the presumptive mesoderm and endoderm at the blastula and gastrula stages and the prechordal mesoderm at later stages. In Xenopus embryos, overexpression of pitx2 caused ectopic expression of goosecoid and sox-17β and interfered with mesoderm formation. Overexpression of pitx2 in Xenopus animal cap explants partially mimics the effects of Nodal overexpression, suggesting that pitx2 is a mediator of Nodal Signaling during specification of the endoderm and prechordal plate, but not during mesoderm induction. We further demonstrate that pitx2 is induced by Nodal Signaling in Xenopus animal caps and that the early expression of zebrafish pitx2 is absent when the Nodal Signaling pathway is inactive. Inhibition of pitx2 function using a chimeric EnR-pitx2 blocked specification of the mesoderm and endoderm and caused severe embryonic defects resembling those seen when Nodal Signaling is inhibited. Following inhibition of pitx2 function, the fate of ventral vegetal blastomeres was shifted from an endodermal to a more mesodermal fate, an effect that was reversed by wild-type pitx2. Finally, we show that inhibition of pitx2 function interferes with the response of cells to Nodal Signaling. Our results provide direct evidence that pitx2 function is required for normal specification of the endodermal and mesodermal germ layers.

Chenbei Chang - One of the best experts on this subject based on the ideXlab platform.

  • tomoregulin 1 tmeff1 inhibits Nodal Signaling through direct binding to the Nodal coreceptor cripto
    Genes & Development, 2003
    Co-Authors: Paul W Harms, Chenbei Chang
    Abstract:

    Transforming growth factor β (TGF-β) signals regulate multiple processes during development and in adult. We recently showed that tomoregulin-1 (TMEFF1), a transmembrane protein, selectively inhibits Nodal but not activin in early Xenopus embryos. Here we report that TMEFF1 binds to the Nodal coreceptor Cripto, but does not associate with either Nodal or the type I ALK (activin receptor-like kinase) 4 receptor in coimmunoprecipitation assays. The inhibition of the Nodal Signaling by TMEFF1 in Xenopus ectodermal explants is rescued with wild-type but not mutant forms of Cripto. Furthermore, we show that the Cripto-FRL1-Cryptic (CFC) domain in Cripto, which is essential for its binding to ALK4, is also important for its interaction with TMEFF1. Our results demonstrate for the first time that Nodal Signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor.

  • Tomoregulin-1 (TMEFF1) inhibits Nodal Signaling through direct binding to the Nodal coreceptor Cripto
    Genes & development, 2003
    Co-Authors: Paul W Harms, Chenbei Chang
    Abstract:

    Transforming growth factor beta (TGF-beta) signals regulate multiple processes during development and in adult. We recently showed that tomoregulin-1 (TMEFF1), a transmembrane protein, selectively inhibits Nodal but not activin in early Xenopus embryos. Here we report that TMEFF1 binds to the Nodal coreceptor Cripto, but does not associate with either Nodal or the type I ALK (activin receptor-like kinase) 4 receptor in coimmunoprecipitation assays. The inhibition of the Nodal Signaling by TMEFF1 in Xenopus ectodermal explants is rescued with wild-type but not mutant forms of Cripto. Furthermore, we show that the Cripto-FRL1-Cryptic (CFC) domain in Cripto, which is essential for its binding to ALK4, is also important for its interaction with TMEFF1. Our results demonstrate for the first time that Nodal Signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor.