Nodal Signaling Is Required for Mesodermal and Ventral but Not For
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Spemann Organizer Transcriptome Induction by Early Beta-Catenin, Wnt
Spemann organizer transcriptome induction by early PNAS PLUS beta-catenin, Wnt, Nodal, and Siamois signals in Xenopus laevis Yi Dinga,b,1, Diego Plopera,b,1, Eric A. Sosaa,b, Gabriele Colozzaa,b, Yuki Moriyamaa,b, Maria D. J. Beniteza,b, Kelvin Zhanga,b, Daria Merkurjevc,d,e, and Edward M. De Robertisa,b,2 aHoward Hughes Medical Institute, University of California, Los Angeles, CA 90095-1662; bDepartment of Biological Chemistry, University of California, Los Angeles, CA 90095-1662; cDepartment of Medicine, University of California, Los Angeles, CA 90095-1662; dDepartment of Microbiology, University of California, Los Angeles, CA 90095-1662; and eDepartment of Human Genetics, University of California, Los Angeles, CA 90095-1662 Contributed by Edward M. De Robertis, February 24, 2017 (sent for review January 17, 2017; reviewed by Juan Larraín and Stefano Piccolo) The earliest event in Xenopus development is the dorsal accumu- Wnt8 mRNA leads to a dorsalized phenotype consisting entirely of lation of nuclear β-catenin under the influence of cytoplasmic de- head structures without trunks and a radial Spemann organizer terminants displaced by fertilization. In this study, a genome-wide (9–11). Similar dorsalizing effects are obtained by incubating approach was used to examine transcription of the 43,673 genes embryos in lithium chloride (LiCl) solution at the 32-cell stage annotated in the Xenopus laevis genome under a variety of con- (12). LiCl mimics the early Wnt signal by inhibiting the enzymatic ditions that inhibit or promote formation of the Spemann orga- activity of glycogen synthase kinase 3 (GSK3) (13), an enzyme nizer signaling center. -
BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells Via Interaction with Acvr2b
MUShare Faculty Publications and Research College of Osteopathic Medicine 1-1-2012 BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells Via Interaction With Acvr2b. Shoichiro Kokabu Laura Gamer Karen Cox Jonathan W. Lowery Ph.D. Marian University - Indianapolis, [email protected] Kunikazu Tsuji See next page for additional authors Follow this and additional works at: https://mushare.marian.edu/com_fp Part of the Cells Commons, and the Genetics and Genomics Commons Recommended Citation Kokabu S, Gamer L, Cox K, Lowery JW, Kunikazu T, Econimedes A, Katagiri T, Rosen V. “BMP3 suppresses osteoblast differentiation of bone marrow stromal cells via interaction with Acvr2b.” Mol Endocrinol. 2012;26(1):87-94. PMC3248326. PMID: 22074949. This Article is brought to you for free and open access by the College of Osteopathic Medicine at MUShare. It has been accepted for inclusion in Faculty Publications and Research by an authorized administrator of MUShare. For more information, please contact [email protected]. Authors Shoichiro Kokabu, Laura Gamer, Karen Cox, Jonathan W. Lowery Ph.D., Kunikazu Tsuji, Regina Raz, Aris Economides, Takenobu Katagiri, and Vicki Rosen This article is available at MUShare: https://mushare.marian.edu/com_fp/12 ORIGINAL RESEARCH BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells via Interaction with Acvr2b Shoichiro Kokabu, Laura Gamer, Karen Cox, Jonathan Lowery, Kunikazu Tsuji, Regina Raz, Aris Economides, Takenobu Katagiri, and Vicki Rosen Department of Developmental Biology (S.K., L.G., K.C., J.L., V.R.), Harvard School of Dental Medicine, Boston, Massachusetts 02115; Section of Orthopedic Surgery (K.T.),Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Regeneron Pharmaceuticals (R.R., A.E.), Tarrytown, New York 10591; and Division of Pathophysiology (T.K.), Saitama Medical University, Saitama 359-8513, Japan Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. -
Follistatin and Noggin Are Excluded from the Zebrafish Organizer
DEVELOPMENTAL BIOLOGY 204, 488–507 (1998) ARTICLE NO. DB989003 Follistatin and Noggin Are Excluded from the Zebrafish Organizer Hermann Bauer,* Andrea Meier,* Marc Hild,* Scott Stachel,†,1 Aris Economides,‡ Dennis Hazelett,† Richard M. Harland,† and Matthias Hammerschmidt*,2 *Max-Planck Institut fu¨r Immunbiologie, Stu¨beweg 51, 79108 Freiburg, Germany; †Department of Molecular and Cell Biology, University of California, 401 Barker Hall 3204, Berkeley, California 94720-3204; and ‡Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591-6707 The patterning activity of the Spemann organizer in early amphibian embryos has been characterized by a number of organizer-specific secreted proteins including Chordin, Noggin, and Follistatin, which all share the same inductive properties. They can neuralize ectoderm and dorsalize ventral mesoderm by blocking the ventralizing signals Bmp2 and Bmp4. In the zebrafish, null mutations in the chordin gene, named chordino, lead to a severe reduction of organizer activity, indicating that Chordino is an essential, but not the only, inductive signal generated by the zebrafish organizer. A second gene required for zebrafish organizer function is mercedes, but the molecular nature of its product is not known as yet. To investigate whether and how Follistatin and Noggin are involved in dorsoventral (D-V) patterning of the zebrafish embryo, we have now isolated and characterized their zebrafish homologues. Overexpression studies demonstrate that both proteins have the same dorsalizing properties as their Xenopus homologues. However, unlike the Xenopus genes, zebrafish follistatin and noggin are not expressed in the organizer region, nor are they linked to the mercedes mutation. Expression of both genes starts at midgastrula stages. -
Secreted Bone Morphogenetic Protein Antagonists of the Chordin Family
Article in press - uncorrected proof BioMol Concepts, Vol. 1 (2010), pp. 297–304 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BMC.2010.026 Review Secreted bone morphogenetic protein antagonists of the Chordin family Nobuyuki Itoha,* and Hiroya Ohtaa factor b (TGFb) superfamily. Originally identified in the Department of Genetic Biochemistry, Kyoto University protein extracts of deminerized bone, BMPs promote endo- Graduate School of Pharmaceutical Sciences, Sakyo, chondral bone formation. However, they also play diverse Kyoto 606-8501, Japan roles in developmental and metabolic processes at the embry- onic and postnatal stages. BMPs are secreted as dimers and * Corresponding author activate specific Ser/Thr kinase receptors at cell surfaces. e-mail: [email protected] The activated receptors propagate BMP signals via the phos- phorylation of Smad proteins and other non-canonical intra- Abstract cellular effectors (1, 2). The actions of BMPs are inhibited by several secreted Chordin, Chordin-like 1, and Chordin-like 2 are secreted BMP antagonists. Most extracellular BMP antagonists inhibit bone morphogenetic protein (BMP) antagonists with highly BMPs by binding to them. The amino acid sequences of conserved Chordin-like cysteine-rich domains. Recently, secreted BMP antagonists are characterized by cysteine-rich Brorin and Brorin-like have been identified as new Chordin- (CR) domains. On the basis of the spacing of cysteine resi- like BMP antagonists. A Chordin ortholog, Short gastrula- dues in the CR domains, secreted BMP antagonists can be tion, has been identified in Drosophila, a protostome, but not classified into five groups; the Dan family, Twisted gastru- other orthologs. -
Inhibition of Activin/Nodal and Wnt Signaling Andrey V
RESEARCH ARTICLE 5345 Development 138, 5345-5356 (2011) doi:10.1242/dev.068908 © 2011. Published by The Company of Biologists Ltd Novel functions of Noggin proteins: inhibition of Activin/Nodal and Wnt signaling Andrey V. Bayramov*, Fedor M. Eroshkin*, Natalia Y. Martynova, Galina V. Ermakova, Elena A. Solovieva and Andrey G. Zaraisky‡ SUMMARY The secreted protein Noggin1 is an embryonic inducer that can sequester TGF cytokines of the BMP family with extremely high affinity. Owing to this function, ectopic Noggin1 can induce formation of the headless secondary body axis in Xenopus embryos. Here, we show that Noggin1 and its homolog Noggin2 can also bind, albeit less effectively, to ActivinB, Nodal/Xnrs and XWnt8, inactivation of which, together with BMP, is essential for the head induction. In support of this, we show that both Noggin proteins, if ectopically produced in sufficient concentrations in Xenopus embryo, can induce a secondary head, including the forebrain. During normal development, however, Noggin1 mRNA is translated in the presumptive forebrain with low efficiency, which provides the sufficient protein concentration for only its BMP-antagonizing function. By contrast, Noggin2, which is produced in cells of the anterior margin of the neural plate at a higher concentration, also protects the developing forebrain from inhibition by ActivinB and XWnt8 signaling. Thus, besides revealing of novel functions of Noggin proteins, our findings demonstrate that specification of the forebrain requires isolation of its cells from BMP, Activin/Nodal and Wnt signaling not only during gastrulation but also at post-gastrulation stages. KEY WORDS: Noggin, Activin, Nodal, Wnt, Forebrain, Xenopus INTRODUCTION laevis embryos, to bind to and antagonize several secreted proteins The secreted protein Noggin (Noggin1) was first discovered in known to be involved in regulation of TGF and Wnt signaling. -
Signal Transduction Pathway Through Activin Receptors As a Therapeutic Target of Musculoskeletal Diseases and Cancer
Endocr. J./ K. TSUCHIDA et al.: SIGNALING THROUGH ACTIVIN RECEPTORS doi: 10.1507/endocrj.KR-110 REVIEW Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer KUNIHIRO TSUCHIDA, MASASHI NAKATANI, AKIYOSHI UEZUMI, TATSUYA MURAKAMI AND XUELING CUI Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan Received July 6, 2007; Accepted July 12, 2007; Released online September 14, 2007 Correspondence to: Kunihiro TSUCHIDA, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and three type I receptors, ALK2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. -
Supplementary Materials
Supplementary Materials + - NUMB E2F2 PCBP2 CDKN1B MTOR AKT3 HOXA9 HNRNPA1 HNRNPA2B1 HNRNPA2B1 HNRNPK HNRNPA3 PCBP2 AICDA FLT3 SLAMF1 BIC CD34 TAL1 SPI1 GATA1 CD48 PIK3CG RUNX1 PIK3CD SLAMF1 CDKN2B CDKN2A CD34 RUNX1 E2F3 KMT2A RUNX1 T MIXL1 +++ +++ ++++ ++++ +++ 0 0 0 0 hematopoietic potential H1 H1 PB7 PB6 PB6 PB6.1 PB6.1 PB12.1 PB12.1 Figure S1. Unsupervised hierarchical clustering of hPSC-derived EBs according to the mRNA expression of hematopoietic lineage genes (microarray analysis). Hematopoietic-competent cells (H1, PB6.1, PB7) were separated from hematopoietic-deficient ones (PB6, PB12.1). In this experiment, all hPSCs were tested in duplicate, except PB7. Genes under-expressed or over-expressed in blood-deficient hPSCs are indicated in blue and red respectively (related to Table S1). 1 C) Mesoderm B) Endoderm + - KDR HAND1 GATA6 MEF2C DKK1 MSX1 GATA4 WNT3A GATA4 COL2A1 HNF1B ZFPM2 A) Ectoderm GATA4 GATA4 GSC GATA4 T ISL1 NCAM1 FOXH1 NCAM1 MESP1 CER1 WNT3A MIXL1 GATA4 PAX6 CDX2 T PAX6 SOX17 HBB NES GATA6 WT1 SOX1 FN1 ACTC1 ZIC1 FOXA2 MYF5 ZIC1 CXCR4 TBX5 PAX6 NCAM1 TBX20 PAX6 KRT18 DDX4 TUBB3 EPCAM TBX5 SOX2 KRT18 NKX2-5 NES AFP COL1A1 +++ +++ 0 0 0 0 ++++ +++ ++++ +++ +++ ++++ +++ ++++ 0 0 0 0 +++ +++ ++++ +++ ++++ 0 0 0 0 hematopoietic potential H1 H1 H1 H1 H1 H1 PB6 PB6 PB7 PB7 PB6 PB6 PB7 PB6 PB6 PB6.1 PB6.1 PB6.1 PB6.1 PB6.1 PB6.1 PB12.1 PB12.1 PB12.1 PB12.1 PB12.1 PB12.1 Figure S2. Unsupervised hierarchical clustering of hPSC-derived EBs according to the mRNA expression of germ layer differentiation genes (microarray analysis) Selected ectoderm (A), endoderm (B) and mesoderm (C) related genes differentially expressed between hematopoietic-competent (H1, PB6.1, PB7) and -deficient cells (PB6, PB12.1) are shown (related to Table S1). -
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. -
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 -
TGF Beta Signaling Pathway 1 TGF Beta Signaling Pathway
TGF beta signaling pathway 1 TGF beta signaling pathway The Transforming growth factor beta (TGFβ) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression. Mechanism Ligand Binding The TGF Beta superfamily of ligands include: Bone morphogenetic proteins (BMPs), Growth and differentiation factors (GDFs), Anti-müllerian hormone (AMH), Activin, Nodal and TGFβ's[1] . Signalling begins with the binding of a TGF beta superfamily ligand to a TGF beta type II receptor. The type II receptor is a serine/threonine receptor kinase, which catalyses the phosphorylation of the Type I receptor. Each class of ligand binds to a specific type II receptor[2] .In mammals there are seven known type I receptors and five type II receptors[3] . There are three activins: Activin A, Activin B and Activin AB. Activins are involved in embryogenesis and osteogenesis. They also regulate many hormones including pituitary, gonadal and hypothalamic hormones as well as insulin. They are also nerve cell survival factors. The BMPs bind to the Bone morphogenetic protein receptor type-2 (BMPR2). -
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). -
The Zinc Finger Gene Xblimp1 Controls Anterior Endomesodermal Cell Fate
The EMBO Journal Vol.18 No.21 pp.6062–6072, 1999 The zinc finger gene Xblimp1 controls anterior endomesodermal cell fate in Spemann’s organizer Fla´ vio S.J.de Souza, Volker Gawantka, give rise to liver, foregut and prechordal endomesoderm Aitana Perea Go´ mez1, Hajo Delius2, (Pasteels, 1949; Nieuwkoop and Florschu¨tz, 1950; Keller, Siew-Lan Ang1 and Christof Niehrs3 1991; Bouwmeester et al., 1996). The activity of one gene expressed in the anterior endomesoderm, cerberus, has Division of Molecular Embryology and 2Division of Applied Tumour given strong molecular support to the idea that this region Virology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld is crucial in the process of head induction (reviewed in 280, D-69120 Heidelberg, Germany and 1Institut de Ge´ne´tique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/Universite´ Louis Slack and Tannahill, 1992; Gilbert and Saxen, 1993; Pasteur/Colle`ge de France, BP163, 67404 Illkirch cedex, Bouwmeester and Leyns, 1997; Niehrs, 1999). Cerberus CU de Strasbourg, France is a secreted factor able to induce ectopic heads including 3Corresponding author forebrain, eye, cement gland and heart in Xenopus (Bouwmeester et al., 1996). Independent evidence for the The anterior endomesoderm of the early Xenopus importance of endoderm in forebrain induction comes gastrula is a part of Spemann’s organizer and is from studies in mouse, where ablation of anterior visceral important for head induction. Here we describe endodermal cells (Thomas and Beddington, 1996) as well Xblimp1, which encodes a zinc finger transcriptional as inactivation of genes such as nodal (Varlet et al., 1997) repressor expressed in the anterior endomesoderm.