DOCSLIB.ORG

Nuclear Movement Regulated by Non-Smad Nodal Signaling Via JNK

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nuclear Movement Regulated by Non-Smad Nodal Signaling Via JNK © 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 4015-4025 doi:10.1242/dev.151746 RESEARCH ARTICLE Nuclear movement regulated by non-Smad Nodal signaling via JNK is associated with Smad signaling during zebrafish endoderm specification Shunya Hozumi, Shun Aoki and Yutaka Kikuchi* ABSTRACT been shown to be involved in nuclear positioning. It has been Asymmetric nuclear positioning is observed during animal suggested that the position of the microtubule-organizing center development, but its regulation and significance in cell differentiation (MTOC) and the connection between the MTOC and the nucleus remain poorly understood. Using zebrafish blastulae, we provide are crucial for MT-mediated nuclear movement (Bone and Starr, evidence that nuclear movement towards the yolk syncytial layer, 2016; Gundersen and Worman, 2013). which comprises extraembryonic tissue, occurs in the first cells fated to Although many studies have suggested that nuclear positioning differentiate into the endoderm. Nodal signaling is essential for nuclear plays an important role in cellular function, only one study has movement, whereas nuclear envelope proteins are involved in reported on the relationship between nuclear positioning, asymmetric movement through microtubule formation. Positioning of the signaling, and cell fate determination (Del Bene et al., 2008; microtubule-organizing center, which is proposed to be crucial for Gundersen and Worman, 2013). In the developing zebrafish retina nuclear movement, is regulated by Nodal signaling and nuclear neuroepithelium, nuclear movement, termed interkinetic nuclear envelope proteins. The non-Smad JNK signaling pathway, which is migration, is correlated with cell cycle exit and Notch signaling downstream of Nodal signaling, regulates nuclear movement activation; this process is regulated by Syne (a LINC complex independently of the Smad pathway, and this nuclear movement is protein) and the motor protein Dynactin 1 (Del Bene et al., 2008; associated with Smad signal transduction toward the nucleus. Our Gundersen and Worman, 2013). However, the exact mechanisms of study provides insight into the function of nuclear movement in Smad nuclear movement, and the relationship between nuclear movement signaling toward the nucleus, and could be applied to the control of and cell fate determination, remain to be elucidated. β β TGFβ signaling. Nodal, a transforming growth factor (TGF ) superfamily member, is a ligand that regulates the expression of its target genes KEY WORDS: Nuclear movement, Endoderm specification, Nodal, by binding to serine/threonine kinase receptors and inducing the Smad, JNK, MTOC phosphorylation of Smad2/3 (Di Guglielmo et al., 2003; Penheiter et al., 2002; Hayes et al., 2002). In mouse and zebrafish embryos, INTRODUCTION Nodal is essential for mesendoderm induction prior to gastrulation The largest organelle, the nucleus, is not always located in the center (Weinstein et al., 1998; Nomura and Li, 1998; Jia et al., 2008). of the cell. Asymmetrical positioning of the nucleus has been Genetic analyses in zebrafish revealed that two Nodal-related genes, observed in differentiated animal cells and tissues, including nodal-related 1 (ndr1) and ndr2, are essential, and that the EGF- skeletal muscle, many epithelial cells, and neurons (Dupin and CFC family gene teratocarcinoma-derived growth factor 1 (tdgf1), Etienne-Manneville, 2011; Gundersen and Worman, 2013). which encodes a co-receptor of Nodal, is necessary for Abnormal positioning leads to cellular dysfunction and diseases, mesendoderm induction (Schier, 2009). In addition, analyses such as muscular dystrophy, cardiomyopathy and lissencephaly using various zebrafish mutants and knockdown experiments have (Gundersen and Worman, 2013; Bone and Starr, 2016). The identified molecular pathways leading to the endoderm cell fate positioning of the nucleus is dynamically regulated during cell (Fukuda and Kikuchi, 2005; Zorn and Wells, 2009). It has been division and migration (Dupin and Etienne-Manneville, 2011; shown that Sox32 (Casanova) is an essential transcription factor for Gundersen and Worman, 2013). Recent studies revealed that endoderm fate determination downstream of Nodal/Smad signaling nuclear positioning is controlled by microtubules (MTs), actins, and (Dickmeis et al., 2001; Kikuchi et al., 2001). Aside from the Smad associated motor proteins. In addition, the linker of nucleoskeleton pathway, TGFβ also activates non-Smad signaling pathways, such and cytoskeleton (LINC) complex, which is composed of outer as extracellular signal-regulated kinase (Erk), p38 (Mapk14) and nuclear membrane KASH-domain (Klarsicht, ANC-1 and Syne c-Jun N-terminal kinase (JNK) (Moustakas and Heldin, 2005; homology) proteins and inner nuclear membrane SUN-domain Derynck and Zhang, 2003; Mu et al., 2012). Smad and non-Smad (Sad1p and UNC-84) proteins (Bone and Starr, 2016; Dupin and signaling pathways are involved in the regulation of various cellular Etienne-Manneville, 2011; Gundersen and Worman, 2013), has processes, including cell differentiation, proliferation, migration and epithelial-mesenchymal transition (EMT) through cell context- dependent transcription and the regulation of cytoskeleton and cell Department of Biological Science, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima, Hiroshima, 739-8526 Japan. junction formation (Moustakas and Heldin, 2005; Derynck and Zhang, 2003; Mu et al., 2012); however, the interactions between *Author for correspondence ([email protected]) these pathways are poorly understood. Y.K., 0000-0001-5688-7358 During the course of our analysis of endoderm specification, we discovered distinct nuclear movement toward the yolk syncytial Received 9 March 2017; Accepted 14 September 2017 layer (YSL) in the most laterally located marginal cells (lateral DEVELOPMENT 4015 RESEARCH ARTICLE Development (2017) 144, 4015-4025 doi:10.1242/dev.151746 marginal cells, or LMCs), which are the first cells fated to (EVL) cells (Fig. 1A, green cell). At 4.7 hpf, 97.7% (43/44) of LMCs differentiate into the endoderm. In this study, we explored the were sox32+ (Fig. 1B,B′, arrowheads). By contrast, medial marginal regulation and significance of nuclear movement in LMCs by Nodal cells (MMCs) (Fig. 1A, red cells), which were adjacent to both LMCs signaling, and identified that the non-Smad JNK signaling pathway and the YSL, did not express sox32 at 4.7 hpf [2.3% (1/44) of MMCs regulates nuclear movement independently of Smad; this movement were sox32+;Fig.1B,B′, arrows], indicating that LMCs are the first leads to transduction of the Smad signal toward the nucleus. endoderm specified cells in zebrafish embryos. Nuclear positioning of LMCs in WT embryos at 4.7 hpf appeared RESULTS to be closer to the YSL as compared with that at 4.0 hpf (Fig. 1B,B′, Nodal signaling is necessary for nuclear movement toward D, arrowheads). In addition, nuclear positioning of LMCs appeared the YSL in the most laterally located marginal cells during to be more distant from the YSL following treatment with the TGFβ endoderm specification type I receptor inhibitors SB505124 or SB431542 (Laping et al., In order to explore the process of endodermal fate determination from 2002; Inman et al., 2002; Callahan et al., 2002; DaCosta Byfield the sphere [4.0 h post fertilization (hpf)] to the late blastula stage et al., 2004), at 4.7 hpf (Fig. 1E,F, arrowheads). This suggests that (4.7 hpf), we carefully observed the spatiotemporal emergence and Nodal signaling is involved in determination of nuclear positioning distribution of sox32-expressing endoderm cells in the marginal in LMCs. Confocal time-lapse analysis clearly showed that while domain of wild-type (WT) embryos using fluorescence in situ the nuclei in both LMCs and MMCs moved toward the YSL, those hybridization (FISH). Expression of sox32 was first detected in in LMCs were closer to the YSL than those in MMCs between 4.0 LMCs located adjacent to both the YSL and the enveloping layer and 4.7 hpf (Movies 1 and 2). Fig. 1. Nuclear movement toward the YSL in LMCs occurs at 4.7 hpf. (A) Illustration of the zebrafish blastula embryo (left) and location of marginal cells (right). LMCs refers to the most laterally located marginal cells (green); MMCs, medial marginal cells (red); EVL, enveloping layer; YSL, yolk syncytial layer; A, animal; V, vegetal; M, medial; L, lateral. (B-F) Transverse sections of wild-type (WT) and TGFβ type I receptor inhibitor (SB505124 or SB431542)-treated embryos. The cell membrane and the nucleus are visualized by β-catenin (β-cat) and DAPI staining, respectively. The endoderm marker sox32 was detected by FISH (B only). Arrows and arrowheads indicate MMCs and LMCs, respectively. (G) Minimum distance between the most vegetal position of the nucleus and the blastoderm/YSL boundary (DNB) in WT and TGFβ receptor inhibitor-treated embryos. (H) Minimum distance between the center of the cell and the most vegetal position of the nucleus (DCN) relative to the animal-vegetal axis in WT and TGFβ receptor inhibitor-treated embryos. In the DCN, the center of the cell is defined as zero; the animal and vegetal sides relative to the center of cell are set as plus and minus along the animal and vegetal axes, respectively. (G,H) ***P<0.001. n, number of nuclei examined. (I) Transverse sections of WT embryos showing mixl1, gata5 and sox32 FISH (green) at 4.7 hpf. DAPI, blue. The number of embryos showing this pattern among the total examined
Load more

Recommended publications
  • Nodal Signaling Is Required for Mesodermal and Ventral but Not For
    © 2015. Published by The Company of Biologists Ltd | Biology Open (2015) 4, 830-842 doi:10.1242/bio.011809 RESEARCH ARTICLE Nodal signaling is required for mesodermal and ventral but not for dorsal fates in the indirect developing hemichordate, Ptychodera flava Eric Röttinger1,2,3,*, Timothy Q. DuBuc4, Aldine R. Amiel1,2,3 and Mark Q. Martindale4 ABSTRACT early fate maps of direct and indirect developing hemichordates, are Nodal signaling plays crucial roles in vertebrate developmental similar to those of indirect-developing echinoids (Colwin and processes such as endoderm and mesoderm formation, and axial Colwin, 1951; Cameron et al., 1987; Cameron et al., 1989; Cameron patterning events along the anteroposterior, dorsoventral and left- and Davidson, 1991; Henry et al., 2001). While the bilaterally right axes. In echinoderms, Nodal plays an essential role in the symmetric echinoderm larvae exhibit strong similarities to establishment of the dorsoventral axis and left-right asymmetry, but chordates in axial patterning and germ layer specification events, not in endoderm or mesoderm induction. In protostomes, Nodal adult body plan comparisons in echinoderms have been difficult due signaling appears to be involved only in establishing left-right to their unique adult pentaradial symmetry. However, both the larval asymmetry. Hence, it is hypothesized that Nodal signaling has and adult body plans of enteropneust hemichordates are bilaterally been co-opted to pattern the dorsoventral axis of deuterostomes and symmetric, and larvae from indirect developing hemichordates for endoderm, mesoderm formation as well as anteroposterior such as Ptychodera flava (P. flava) share similarities in patterning in chordates. Hemichordata, together with echinoderms, morphology, axial organization, and developmental fate map with represent the sister taxon to chordates.
    [Show full text]
  • Cerberus–Nodal–Lefty–Pitx Signaling Cascade Controls Left–Right Asymmetry in Amphioxus
    Cerberus–Nodal–Lefty–Pitx signaling cascade controls left–right asymmetry in amphioxus Guang Lia,1, Xian Liua,1, Chaofan Xinga, Huayang Zhanga, Sebastian M. Shimeldb,2, and Yiquan Wanga,2 aState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; and bDepartment of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom Edited by Marianne Bronner, California Institute of Technology, Pasadena, CA, and approved February 21, 2017 (received for review December 14, 2016) Many bilaterally symmetrical animals develop genetically pro- Several studies have sought to dissect the evolutionary history of grammed left–right asymmetries. In vertebrates, this process is un- Nodal signaling and its regulation of LR asymmetry. Notably, der the control of Nodal signaling, which is restricted to the left side asymmetric expression of Nodal and Pitx in gastropod mollusc by Nodal antagonists Cerberus and Lefty. Amphioxus, the earliest embryos plays a role in the development of LR asymmetry, in- diverging chordate lineage, has profound left–right asymmetry as cluding the coiling of the shell (5, 6). Asymmetric expression of alarva.WeshowthatCerberus, Nodal, Lefty, and their target Nodal and/or Pitx has also been reported in some other lopho- transcription factor Pitx are sequentially activated in amphioxus trochozoans, including Pitx in a brachiopod and an annelid and embryos. We then address their function by transcription activa- Nodal in a brachiopod (7, 8). These data can be interpreted to tor-like effector nucleases (TALEN)-based knockout and heat-shock suggest an ancestral role for Nodal and Pitx in regulating bilat- promoter (HSP)-driven overexpression.
    [Show full text]
  • The Genetic Factors of Bilaterian Evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen a Panfilio2,3, Thomas Wiehe1
    RESEARCH ARTICLE The genetic factors of bilaterian evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen A Panfilio2,3, Thomas Wiehe1 1Institute for Genetics, Cologne Biocenter, University of Cologne, Cologne, Germany; 2Institute for Zoology: Developmental Biology, Cologne Biocenter, University of Cologne, Cologne, Germany; 3School of Life Sciences, University of Warwick, Gibbet Hill Campus, Coventry, United Kingdom Abstract The Cambrian explosion was a unique animal radiation ~540 million years ago that produced the full range of body plans across bilaterians. The genetic mechanisms underlying these events are unknown, leaving a fundamental question in evolutionary biology unanswered. Using large-scale comparative genomics and advanced orthology evaluation techniques, we identified 157 bilaterian-specific genes. They include the entire Nodal pathway, a key regulator of mesoderm development and left-right axis specification; components for nervous system development, including a suite of G-protein-coupled receptors that control physiology and behaviour, the Robo- Slit midline repulsion system, and the neurotrophin signalling system; a high number of zinc finger transcription factors; and novel factors that previously escaped attention. Contradicting the current view, our study reveals that genes with bilaterian origin are robustly associated with key features in extant bilaterians, suggesting a causal relationship. *For correspondence: [email protected] Introduction The taxon Bilateria consists of multicellular animals
    [Show full text]
  • ISM1 Regulates NODAL Signaling and Asymmetric Organ Morphogenesis During Development
    Published Online: 6 June, 2019 | Supp Info: http://doi.org/10.1083/jcb.201801081 Downloaded from jcb.rupress.org on June 6, 2019 ARTICLE ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development Liliana Osório1,2*,XueweiWu1,2*, Linsheng Wang1,2*, Zhixin Jiang1,2,CarlosNeideck1,2, Guojun Sheng3,4, and Zhongjun Zhou1,2 Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL–ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling. Introduction The TGF-β superfamily includes a large number of secreted whereas GDF3 is an essential coligand for NODAL signaling in signaling factors that are essential for embryonic development, germ layer formation and LR patterning during early develop- tissue homeostasis, and human diseases such as cancer ment (Levine et al., 2009; Peterson et al., 2013; Pelliccia et al., (Wakefield and Hill, 2013).
    [Show full text]
  • TGF-Β Signaling
    biomolecules Review TGF-β Signaling Kalliopi Tzavlaki and Aristidis Moustakas * Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden; [email protected] * Correspondence: [email protected]; Tel.: +46-18-4714732; Fax: +46-18-4714441 Received: 18 February 2020; Accepted: 20 March 2020; Published: 23 March 2020 Abstract: Transforming growth factor-β (TGF-β) represents an evolutionarily conserved family of secreted polypeptide factors that regulate many aspects of physiological embryogenesis and adult tissue homeostasis. The TGF-β family members are also involved in pathophysiological mechanisms that underlie many diseases. Although the family comprises many factors, which exhibit cell type-specific and developmental stage-dependent biological actions, they all signal via conserved signaling pathways. The signaling mechanisms of the TGF-β family are controlled at the extracellular level, where ligand secretion, deposition to the extracellular matrix and activation prior to signaling play important roles. At the plasma membrane level, TGF-βs associate with receptor kinases that mediate phosphorylation-dependent signaling to downstream mediators, mainly the SMAD proteins, and mediate oligomerization-dependent signaling to ubiquitin ligases and intracellular protein kinases. The interplay between SMADs and other signaling proteins mediate regulatory signals that control expression of target genes, RNA processing at multiple levels, mRNA translation and nuclear or cytoplasmic protein regulation. This article emphasizes signaling mechanisms and the importance of biochemical control in executing biological functions by the prototype member of the family, TGF-β. Keywords: extracellular matrix; phosphorylation; receptor serine/threonine kinase; signal transduction; SMAD; transcription; transforming growth factor-β; ubiquitylation 1.
    [Show full text]
  • Vg1-Nodal Heterodimers Are the Endogenous Inducers of Mesendoderm Tessa G Montague1*, Alexander F Schier1,2,3,4,5*
    RESEARCH ARTICLE Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm Tessa G Montague1*, Alexander F Schier1,2,3,4,5* 1Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; 2Center for Brain Science, Harvard University, Cambridge, United States; 3Broad Institute of MIT and Harvard, Cambridge, United States; 4Harvard Stem Cell Institute, Cambridge, United States; 5FAS Center for Systems Biology, Harvard University, Cambridge, United States Abstract Nodal is considered the key inducer of mesendoderm in vertebrate embryos and embryonic stem cells. Other TGF-beta-related signals, such as Vg1/Dvr1/Gdf3, have also been implicated in this process but their roles have been unclear or controversial. Here we report that zebrafish embryos without maternally provided vg1 fail to form endoderm and head and trunk mesoderm, and closely resemble nodal loss-of-function mutants. Although Nodal is processed and secreted without Vg1, it requires Vg1 for its endogenous activity. Conversely, Vg1 is unprocessed and resides in the endoplasmic reticulum without Nodal, and is only secreted, processed and active in the presence of Nodal. Co-expression of Nodal and Vg1 results in heterodimer formation and mesendoderm induction. Thus, mesendoderm induction relies on the combination of two TGF-beta- related signals: maternal and ubiquitous Vg1, and zygotic and localized Nodal. Modeling reveals that the pool of maternal Vg1 enables rapid signaling at low concentrations of zygotic Nodal. DOI: https://doi.org/10.7554/eLife.28183.001 Introduction *For correspondence: tessa. [email protected] (TGM); The induction of mesoderm and endoderm (mesendoderm) during embryogenesis and embryonic [email protected] (AFS) stem cell differentiation generates the precursors of the heart, liver, gut, pancreas, kidney and other internal organs.
    [Show full text]
  • The New Role of TGF-Β Superfamily Signaling in Melanoma
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 The new role of TGF-฀ superfamily signaling in melanoma Tuncer, Eylül Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148195 Dissertation Published Version Originally published at: Tuncer, Eylül. The new role of TGF-฀ superfamily signaling in melanoma. 2017, University of Zurich, Faculty of Science. The New Role of TGF-β Superfamily Signaling in Melanoma Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Eylül Tuncer Aus der Türkei Promotionskommission Prof. Dr. Lukas Sommer (Leitung und Vorsitz der Dissertation) Prof. Dr. med. Onur Boyman Prof. Dr. med. Markus Manz Prof. Dr. Burkhard Becher Zürich, 2017 Table of Contents Table of Contents ......................................................................................................... 2 1. Summary .................................................................................................................. 5 2. Zusammenfassung ..................................................................................................... 6 3. Introduction .............................................................................................................. 8 3.1 Definition and Epidemiology of Cutaneous Melanoma ................................................ 8 3.2 Clinical
    [Show full text]
  • The Regulation of Mesodermal Progenitor Cell Commitment to Somitogenesis Subdivides the Zebrafish Body Musculature Into Distinct Domains
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press The regulation of mesodermal progenitor cell commitment to somitogenesis subdivides the zebrafish body musculature into distinct domains Daniel P. Szeto1 and David Kimelman2 Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA The vertebrate musculature is produced from a visually uniform population of mesodermal progenitor cells (MPCs) that progressively bud off somites populating the trunk and tail. How the MPCs are regulated to continuously release cells into the presomitic mesoderm throughout somitogenesis is not understood. Using a genetic approach to study the MPCs, we show that a subset of MPCs are set aside very early in zebrafish development, and programmed to cell-autonomously enter the tail domain beginning with the 16th somite. Moreover, we show that the trunk is subdivided into two domains, and that entry into the anterior trunk, posterior trunk, and tail is regulated by interactions between the Nodal and bone morphogenetic protein (Bmp) pathways. Finally, we show that the tail MPCs are held in a state we previously called the Maturation Zone as they wait for the signal to begin entering somitogenesis. [Keywords: Bmp signaling; Nodal; T-box genes; MZoep; somite] Supplemental material is available at http://www.genesdev.org. Received March 29, 2006; revised version accepted May 12, 2006. The mesodermal progenitor cells (MPCs) are a popula- the presomitic mesoderm (Griffin and Kimelman 2002) tion of undifferentiated progenitor cells that originate in (this zone is not the same as the maturation front at the the early gastrula embryo (for review, see Schier et al.
    [Show full text]
  • Reproductionreview
    REPRODUCTIONREVIEW Focus on TGF-b Signalling The structural basis of TGF-b, bone morphogenetic protein, and activin ligand binding S Jack Lin1, Thomas F Lerch2, Robert W Cook1, Theodore S Jardetzky2 and Teresa K Woodruff1,3 1Department of Neurobiology and Physiology, 2Department of Biochemistry, Molecular Biology and Cell Biology, 3Department of Medicine, Northwestern University, 2205 Tech Drive, Evanston, IL 60208, USA Correspondence should be addressed to T K Woodruff; Email: [email protected] Abstract The transforming growth factor-b (TGF-b) superfamily is a large group of structurally related growth factors that play prominent roles in a variety of cellular processes. The importance and prevalence of TGF-b signaling are also reflected by the complex network of check points that exist along the signaling pathway, including a number of extracellular antagonists and membrane- level signaling modulators. Recently, a number of important TGF-b crystal structures have emerged and given us an unprecedented clarity on several aspects of the signal transduction process. This review will highlight these latest advances and present our current understanding on the mechanisms of specificity and regulation on TGF-b signaling outside the cell. Reproduction (2006) 132 179–190 Introduction expressed in tissue-specific patterns and can function in an endocrine, paracrine, and autocrine manner. The transforming growth factor-b (TGF-b) superfamily is Receptor specificity, tissue distribution, and expression a large group of structurally related ligands that regulate levels may all affect the resultant cellular responses. a variety of cellular processes, including cell-cycle Cellular responses to most TGF-b ligands are progression, cell differentiation, reproductive function, transduced through interactions with two single mem- development, motility, adhesion, neuronal growth, bone brane-spanning serine–threonine kinase receptors, morphogenesis, wound healing, and immune surveil- lance (reviewed in Kingsley 1994, Hogan 1996, called type I and type II receptors (Derynck 1994).
    [Show full text]
  • Activins and Inhibins: Roles in Development, Physiology, and Disease
    Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Activins and Inhibins: Roles in Development, Physiology, and Disease Maria Namwanje1 and Chester W. Brown1,2,3 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 2Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 3Texas Children’s Hospital, Houston, Texas 77030 Correspondence: [email protected] Since their original discovery as regulators of follicle-stimulating hormone (FSH) secretion and erythropoiesis, the TGF-b family members activin and inhibin have been shown to participate in a variety of biological processes, from the earliest stages of embryonic devel- opment to highly specialized functions in terminally differentiated cells and tissues. Herein, we present the history, structures, signaling mechanisms, regulation, and biological process- es in which activins and inhibins participate, including several recently discovered biolog- ical activities and functional antagonists. The potential therapeutic relevance of these advances is also discussed. INTRODUCTION, HISTORY AND which the activins and inhibins participate, rep- NOMENCLATURE resenting some of the most fascinating aspects of TGF-b family biology. We will also incorporate he activins and inhibins are among the 33 new biological activities that have been recently Tmembers of the TGF-b family and were first discovered, the potential clinical relevance of described as regulators of follicle-stimulating
    [Show full text]
  • A Nodal- and ALK4-Independent Signaling Pathway Activated by Cripto-1 Through Glypican-1 and C-Src1
    [CANCER RESEARCH 63, 1192–1197, March 15, 2003] Advances in Brief A Nodal- and ALK4-independent Signaling Pathway Activated by Cripto-1 through Glypican-1 and c-Src1 Caterina Bianco, Luigi Strizzi, Aasia Rehman, Nicola Normanno, Christian Wechselberger, Youping Sun, Nadia Khan, Morihisa Hirota, Heather Adkins, Kevin Williams, Richard U. Margolis, Michele Sanicola, and David S. Salomon2 Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [C. B., L. S., A. R., Y. S., N. K., M. H., D. S. S.]; Experimental Oncology B Unit, Istituto Fondazione Pascale, Naples 80131, Italy [N. N.]; Upper Austrian Research GmbH Zentrum, Linz 4020, Austria [C. W.]; Biogen, Inc., Cambridge, Massachusetts 02142 [H. A., K. W., M. S.]; and Department of Pharmacology, New York University Medical Center, New York, New York 10016 [R. U. M.] Abstract ␤-related peptide ligand Nodal, signaling through the type II and type I (ALK4) serine/threonine kinase receptor complex that subsequently Human Cripto-1 (CR-1) is a member of the epidermal growth factor- induces Smad-2, Smad-3, and Smad-4 activation (5). In agreement Cripto FRL1 Cryptic family that has been shown to function as a core- with these results, we have cloned and identified ALK4 as a receptor ceptor with the type I Activin serine-threonine kinase receptor ALK4 for the transforming growth factor ␤-related peptide Nodal. However, CR-1 for CR-1 in mammalian cells (4). However, we found that activation can also activate the mitogen-activated protein kinase and Akt pathways of the ras/raf/MAPK and PI3K/Akt pathways by CR-1 is independent independently of Nodal and ALK4 by an unknown mechanism.
    [Show full text]
  • DISSECTING the EXTRACELLULAR MECHANISMS of NODAL and ACTIVIN SIGNALING REGULATION by Senem Aykul a DISSERTATION Submitted To
    DISSECTING THE EXTRACELLULAR MECHANISMS OF NODAL AND ACTIVIN SIGNALING REGULATION By Senem Aykul A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Biochemistry and Molecular Biology – Doctor of Philosophy 2017 ABSTRACT DISSECTING THE EXTRACELLULAR MECHANISMS OF NODAL AND ACTIVIN SIGNALING REGULATION By Senem Aykul Transforming Growth Factor-β (TGF-β) family ligands are key regulators of multiple cellular processes including cell proliferation, differentiation, and death. Dysregulation of TGF-β family signaling thus contributes to many human diseases, including cancers, fibrosis, and musculoskeletal disorders. Because of its roles in human diseases, understanding the mechanism and regulation of TGF-β family signal transduction is essential and will help the development of new therapeutic agents that could be used to target the family for treating a number of devastating diseases. The basic mechanisms of TGF-β family action are well established. A dimeric ligand binds two ‘type I’ and two ‘type II’ receptors to form a hexameric complex. Assembly of the ligand-receptor complex in the extracellular space leads to phosphorylation of SMAD transcription factors in the intracellular space, their translocation to the nucleus, and expression of target genes. However, beyond ligands and receptors, many additional factors contribute critically to physiological TGF-β family signaling, including membrane-bound co- receptors, secreted inhibitors, and other ligands that are present on or near the surface of a cell. Elucidating the molecular interplay of all the components that form the TGF-β signal transduction system of a particular cell type or tissue is essential for understanding TGF-β signaling in a cellular context.
    [Show full text]