Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 15 (15): 2010-2022

Copyright © 2001 by Cold Spring Harbor Laboratory Press.

Vol. 15, No. 15, pp. 2010-2022, August 1, 2001

The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development

Eva Reissmann,1,2 Henrik Jörnvall,1,4 Andries Blokzijl,1,4 Olov Andersson,1 Chenbei Chang,2 Gabriella Minchiotti,3 M. Graziella Persico,3 Carlos F. Ibáñez,1,5 and Ali H. Brivanlou2

1 Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, S-17177 Stockholm, Sweden; 2 Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, New York 10021-6399, USA; 3 International Institute of Genetics and Biophysics, CNR, 80125 Naples, Italy

Nodal proteins have crucial roles in mesendoderm formation and left-right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1). Receptor reconstitution experiments indicate that ALK7 collaborates with ActRIIB to confer responsiveness to Xnr1 and Nodal. Both receptors can independently bind Xnr1. In addition, Cripto, an extracellular protein genetically implicated in Nodal signaling, can independently interact with both Xnr1 and ALK7, and its expression greatly enhances the ability of ALK7 and ActRIIB to respond to Nodal ligands. The Activin receptor ALK4 is also able to mediate Nodal signaling but only in the presence of Cripto, with which it can also interact directly. A constitutively activated form of ALK7 mimics the mesendoderm-inducing activity of Xnr1 in Xenopus embryos, whereas a dominant-negative ALK7 specifically blocks the activities of Nodal and Xnr1 but has little effect on other related ligands. In contrast, a dominant-negative ALK4 blocks all mesoderm-inducing ligands tested, including Nodal, Xnr1, Xnr2, Xnr4, and Activin. In agreement with a role in Nodal signaling, ALK7 mRNA is localized to the ectodermal and organizer regions of Xenopus gastrula embryos and is expressed during early stages of mouse embryonic development. Therefore, our results indicate that both ALK4 and ALK7 can mediate signal transduction by Nodal proteins, although ALK7 appears to be a receptor more specifically dedicated to Nodal signaling.

[Key Words: Mesendoderm; TGF-beta ; ActRIIB; Xnr1; Oep; Cripto]

4 These authors contributed equally to this work.

5 Corresponding author.

GENES & DEVELOPMENT 15:2010-2022 © 2001 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/01 $5.00

A role for Vg1/Nodal signaling in specification of the intermediate mesoderm.
B. M. Fleming, R. Yelin, R. G. James, and T. M. Schultheiss (2013)
Development 140, 1819-1829
   Abstract »    Full Text »    PDF »
NODAL signaling components regulate essential events in the establishment of pregnancy.
C. B. Park and D. Dufort (2013)
Reproduction 145, R55-R64
   Abstract »    Full Text »    PDF »
Cytoplasmic mislocalization of p27 and CDK2 mediates the anti-migratory and anti-proliferative effects of Nodal in human trophoblast cells.
L. Nadeem, J. Brkic, Y. F. Chen, T. Bui, S. Munir, and C. Peng (2013)
J. Cell Sci. 126, 445-453
   Abstract »    Full Text »    PDF »
Nodal/activin signaling promotes male germ cell fate and suppresses female programming in somatic cells.
Q. Wu, K. Kanata, R. Saba, C.-X. Deng, H. Hamada, and Y. Saga (2013)
Development 140, 291-300
   Abstract »    Full Text »    PDF »
Neuroendocrine control of female reproductive function by the activin receptor ALK7.
T. Sandoval-Guzman, C. Gongrich, A. Moliner, T. Guo, H. Wu, C. Broberger, and C. F. Ibanez (2012)
FASEB J 26, 4966-4976
   Abstract »    Full Text »    PDF »
Whole-genome microRNA screening identifies let-7 and mir-18 as regulators of germ layer formation during early embryogenesis.
A. R. Colas, W. L. McKeithan, T. J. Cunningham, P. J. Bushway, L. X. Garmire, G. Duester, S. Subramaniam, and M. Mercola (2012)
Genes & Dev. 26, 2567-2579
   Abstract »    Full Text »    PDF »
Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin.
O. Guardiola, P. Lafuste, S. Brunelli, S. Iaconis, T. Touvier, P. Mourikis, K. De Bock, E. Lonardo, G. Andolfi, A. Bouche, et al. (2012)
PNAS 109, E3231-E3240
   Abstract »    Full Text »    PDF »
Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 {beta}-cells.
F. Zhao, F. Huang, M. Tang, X. Li, N. Zhang, A. Amfilochiadis, Y. Li, R. Hu, T. Jin, C. Peng, et al. (2012)
Am J Physiol Endocrinol Metab 303, E132-E143
   Abstract »    Full Text »    PDF »
Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling.
M. K.-d. Julio, M. J. Alvarez, A. Galli, J. Chu, S. M. Price, A. Califano, and M. M. Shen (2011)
Development 138, 3885-3895
   Abstract »    Full Text »    PDF »
Nodal Expression in the Uterus of the Mouse Is Regulated by the Embryo and Correlates with Implantation.
C. B. Park and D. Dufort (2011)
Biol Reprod 84, 1103-1110
   Abstract »    Full Text »    PDF »
Toxoplasma gondii Activates Hypoxia-inducible Factor (HIF) by Stabilizing the HIF-1{alpha} Subunit via Type I Activin-like Receptor Kinase Receptor Signaling.
M. Wiley, K. R. Sweeney, D. A. Chan, K. M. Brown, C. McMurtrey, E. W. Howard, A. J. Giaccia, and I. J. Blader (2010)
J. Biol. Chem. 285, 26852-26860
   Abstract »    Full Text »    PDF »
Nodal Morphogens.
A. F. Schier (2009)
Cold Spring Harb Perspect Biol 1, a003459
   Abstract »    Full Text »    PDF »
G Protein-Coupled Receptor APJ and Its Ligand Apelin Act Downstream of Cripto to Specify Embryonic Stem Cells Toward the Cardiac Lineage Through Extracellular Signal-Regulated Kinase/p70S6 Kinase Signaling Pathway.
C. D'Aniello, E. Lonardo, S. Iaconis, O. Guardiola, A. M. Liguoro, G. L. Liguori, M. Autiero, P. Carmeliet, and G. Minchiotti (2009)
Circ. Res. 105, 231-238
   Abstract »    Full Text »    PDF »
Cripto Localizes Nodal at the Limiting Membrane of Early Endosomes.
M.-H. Blanchet, J. A. Le Good, V. Oorschot, S. Baflast, G. Minchiotti, J. Klumperman, and D. B. Constam (2008)
Science Signaling 1, ra13
   Abstract »    Full Text »    PDF »
Cyclin G2 Is Degraded through the Ubiquitin-Proteasome Pathway and Mediates the Antiproliferative Effect of Activin Receptor-like Kinase 7.
G. Xu, S. Bernaudo, G. Fu, D. Y. Lee, B. B. Yang, and C. Peng (2008)
Mol. Biol. Cell 19, 4968-4979
   Abstract »    Full Text »    PDF »
Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.
M.-H. Blanchet, J. A. Le Good, D. Mesnard, V. Oorschot, S. Baflast, G. Minchiotti, J. Klumperman, and D. B. Constam (2008)
EMBO J. 27, 2580-2591
   Abstract »    Full Text »    PDF »
The pro-domain of the zebrafish Nodal-related protein Cyclops regulates its signaling activities.
J. Tian, B. Andree, C. M. Jones, and K. Sampath (2008)
Development 135, 2649-2658
   Abstract »    Full Text »    PDF »
Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity.
O. Andersson, M. Korach-Andre, E. Reissmann, C. F. Ibanez, and P. Bertolino (2008)
PNAS 105, 7252-7256
   Abstract »    Full Text »    PDF »
Activin B receptor ALK7 is a negative regulator of pancreatic {beta}-cell function.
P. Bertolino, R. Holmberg, E. Reissmann, O. Andersson, P.-O. Berggren, and C. F. Ibanez (2008)
PNAS 105, 7246-7251
   Abstract »    Full Text »    PDF »
A Novel Transforming Growth Factor {beta} Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma.
H. Kawajiri, M. Yashiro, O. Shinto, K. Nakamura, M. Tendo, S. Takemura, M. Node, Y. Hamashima, T. Kajimoto, T. Sawada, et al. (2008)
Clin. Cancer Res. 14, 2850-2860
   Abstract »    Full Text »    PDF »
Cripto promotes A-P axis specification independently of its stimulatory effect on Nodal autoinduction.
D. D'Andrea, G. L. Liguori, J. A. Le Good, E. Lonardo, O. Andersson, D. B. Constam, M. G. Persico, and G. Minchiotti (2008)
J. Cell Biol. 180, 597-605
   Abstract »    Full Text »    PDF »
Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination.
C. V. Esguerra, L. Nelles, L. Vermeire, A. Ibrahimi, A. D. Crawford, R. Derua, E. Janssens, E. Waelkens, P. Carmeliet, D. Collen, et al. (2007)
Development 134, 4381-4393
   Abstract »    Full Text »    PDF »
Neural induction requires continued suppression of both Smad1 and Smad2 signals during gastrulation.
C. Chang and R. M. Harland (2007)
Development 134, 3861-3872
   Abstract »    Full Text »    PDF »
Nodal signalling and apoptosis.
H. Wang and B. K Tsang (2007)
Reproduction 133, 847-853
   Abstract »    Full Text »    PDF »
Nodal signaling: developmental roles and regulation.
M. M. Shen (2007)
Development 134, 1023-1034
   Abstract »    Full Text »    PDF »
Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration.
J. Luo, A. H. Lin, E. Masliah, and T. Wyss-Coray (2006)
PNAS 103, 18326-18331
   Abstract »    Full Text »    PDF »
All in the family: TGF-{beta} family action in testis development..
C. Itman, S. Mendis, B. Barakat, and K. L. Loveland (2006)
Reproduction 132, 233-246
   Abstract »    Full Text »    PDF »
Growth differentiation factor 11 signals through the transforming growth factor-{beta} receptor ALK5 to regionalize the anterior-posterior axis.
O. Andersson, E. Reissmann, and C. F. Ibanez (2006)
EMBO Rep. 7, 831-837
   Abstract »    Full Text »    PDF »
Objective prioritization of positional candidate genes at a quantitative trait locus for pre-eclampsia on 2q22.
E.K. Moses, E. Fitzpatrick, K.A. Freed, T.D. Dyer, S. Forrest, K. Elliott, M.P. Johnson, J. Blangero, and S.P. Brennecke (2006)
Mol. Hum. Reprod. 12, 505-512
   Abstract »    Full Text »    PDF »
Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands.
S. Mazerbourg and A. J.W. Hsueh (2006)
Hum. Reprod. Update 12, 373-383
   Abstract »    Full Text »    PDF »
Activin Receptor-Like Kinase 7 Induces Apoptosis through Up-Regulation of Bax and Down-Regulation of Xiap in Normal and Malignant Ovarian Epithelial Cell Lines.
G. Xu, H. Zhou, Q. Wang, N. Auersperg, and C. Peng (2006)
Mol. Cancer Res. 4, 235-246
   Abstract »    Full Text »    PDF »
The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo.
C. Chen, S. M. Ware, A. Sato, D. E. Houston-Hawkins, R. Habas, M. M. Matzuk, M. M. Shen, and C. W. Brown (2006)
Development 133, 319-329
   Abstract »    Full Text »    PDF »
XCR2, one of three Xenopus EGF-CFC genes, has a distinct role in the regulation of left-right patterning.
Y. Onuma, C.-Y. Yeo, and M. Whitman (2006)
Development 133, 237-250
   Abstract »    Full Text »    PDF »
Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis.
J. Chu, J. Ding, K. Jeays-Ward, S. M. Price, M. Placzek, and M. M. Shen (2005)
Development 132, 5539-5551
   Abstract »    Full Text »    PDF »
Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells.
L. Vallier, M. Alexander, and R. A. Pedersen (2005)
J. Cell Sci. 118, 4495-4509
   Abstract »    Full Text »    PDF »
Identification of Receptors and Signaling Pathways for Orphan Bone Morphogenetic Protein/Growth Differentiation Factor Ligands Based on Genomic Analyses.
S. Mazerbourg, K. Sangkuhl, C.-W. Luo, S. Sudo, C. Klein, and A. J. W. Hsueh (2005)
J. Biol. Chem. 280, 32122-32132
   Abstract »    Full Text »    PDF »
Global Analysis of Smad2/3-Dependent TGF-{beta} Signaling in Living Mice Reveals Prominent Tissue-Specific Responses to Injury.
A. H. Lin, J. Luo, L. H. Mondshein, P. ten Dijke, D. Vivien, C. H. Contag, and T. Wyss-Coray (2005)
J. Immunol. 175, 547-554
   Abstract »    Full Text »    PDF »
ALK7, a Receptor for Nodal, Is Dispensable for Embryogenesis and Left-Right Patterning in the Mouse.
H. Jornvall, E. Reissmann, O. Andersson, M. Mehrkash, and C. F. Ibanez (2004)
Mol. Cell. Biol. 24, 9383-9389
   Abstract »    Full Text »    PDF »
Nodal and ALK7 Inhibit Proliferation and Induce Apoptosis in Human Trophoblast Cells.
S. Munir, G. Xu, Y. Wu, B. Yang, P. K. Lala, and C. Peng (2004)
J. Biol. Chem. 279, 31277-31286
   Abstract »    Full Text »    PDF »
Activin Receptor-like Kinase-7 Induces Apoptosis through Activation of MAPKs in a Smad3-dependent Mechanism in Hepatoma Cells.
B.-C. Kim, H. van Gelder, T. A. Kim, H.-J. Lee, K. G. Baik, H. H. Chun, D. A. Lee, K. S. Choi, and S.-J. Kim (2004)
J. Biol. Chem. 279, 28458-28465
   Abstract »    Full Text »    PDF »
Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo.
N. R. Dunn, S. D. Vincent, L. Oxburgh, E. J. Robertson, and E. K. Bikoff (2004)
Development 131, 1717-1728
   Abstract »    Full Text »    PDF »
SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptors ALK4, ALK5, and ALK7.
S. DaCosta Byfield, C. Major, N. J. Laping, and A. B. Roberts (2004)
Mol. Pharmacol. 65, 744-752
   Abstract »    Full Text »    PDF »
Endogenous TGF-{beta} signaling suppresses maturation of osteoblastic mesenchymal cells.
S. Maeda, M. Hayashi, S. Komiya, T. Imamura, and K. Miyazono (2004)
EMBO J. 23, 552-563
   Abstract »    Full Text »    PDF »
Nodal and Fgf pathways interact through a positive regulatory loop and synergize to maintain mesodermal cell populations.
J. Mathieu, K. Griffin, P. Herbomel, T. Dickmeis, U. Strahle, D. Kimelman, F. M. Rosa, and N. Peyrieras (2004)
Development 131, 629-641
   Abstract »    Full Text »    PDF »
Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto.
P. W. Harms and C. Chang (2003)
Genes & Dev. 17, 2624-2629
   Abstract »    Full Text »    PDF »
Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells.
S. Parisi, D. D'Andrea, C. T. Lago, E. D. Adamson, M. G. Persico, and G. Minchiotti (2003)
J. Cell Biol. 163, 303-314
   Abstract »    Full Text »    PDF »
Myostatin Signals through a Transforming Growth Factor {beta}-Like Signaling Pathway To Block Adipogenesis.
A. Rebbapragada, H. Benchabane, J. L. Wrana, A. J. Celeste, and L. Attisano (2003)
Mol. Cell. Biol. 23, 7230-7242
   Abstract »    Full Text »    PDF »
Identification of Novel Isoforms of Activin Receptor-Like Kinase 7 (ALK7) Generated by Alternative Splicing and Expression of ALK7 and Its Ligand, Nodal, in Human Placenta.
H. J. Roberts, S. Hu, Q. Qiu, P. C.K. Leung, I. Caniggia, A. Gruslin, B. Tsang, and C. Peng (2003)
Biol Reprod 68, 1719-1726
   Abstract »    Full Text »    PDF »
Cripto forms a complex with activin and type II activin receptors and can block activin signaling.
P. C. Gray, C. A. Harrison, and W. Vale (2003)
PNAS 100, 5193-5198
   Abstract »    Full Text »    PDF »
BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo.
T. Schlange, H.-H. Arnold, and T. Brand (2003)
Development 129, 3421-3429
   Abstract »    Full Text »    PDF »
EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1.
S. K. Cheng, F. Olale, J. T. Bennett, A. H. Brivanlou, and A. F. Schier (2003)
Genes & Dev. 17, 31-36
   Abstract »    Full Text »    PDF »
Cripto, a Multifunctional Partner in Signaling: Molecular Forms and Activities.
F. M. Rosa (2002)
Sci. STKE 2002, pe47
   Abstract »    Full Text »    PDF »
Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning.
S. P. Oh, C.-Y. Yeo, Y. Lee, H. Schrewe, M. Whitman, and E. Li (2002)
Genes & Dev. 16, 2749-2754
   Abstract »    Full Text »    PDF »
Functions of Transforming Growth Factor-beta Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes.
U. Valcourt, J. Gouttenoire, A. Moustakas, D. Herbage, and F. Mallein-Gerin (2002)
J. Biol. Chem. 277, 33545-33558
   Abstract »    Full Text »    PDF »
Dual Roles of Cripto as a Ligand and Coreceptor in the Nodal Signaling Pathway.
Y.-T. Yan, J.-J. Liu, Y. Luo, C. E, R. S. Haltiwanger, C. Abate-Shen, and M. M. Shen (2002)
Mol. Cell. Biol. 22, 4439-4449
   Abstract »    Full Text »    PDF »
SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-{beta} Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7.
G. J. Inman, F. J. Nicolas, J. F. Callahan, J. D. Harling, L. M. Gaster, A. D. Reith, N. J. Laping, and C. S. Hill (2002)
Mol. Pharmacol. 62, 65-74
   Abstract »    Full Text »    PDF »
Cripto-1 Activates Nodal- and ALK4-Dependent and -Independent Signaling Pathways in Mammary Epithelial Cells.
C. Bianco, H. B. Adkins, C. Wechselberger, M. Seno, N. Normanno, A. De Luca, Y. Sun, N. Khan, N. Kenney, A. Ebert, et al. (2002)
Mol. Cell. Biol. 22, 2586-2597
   Abstract »    Full Text »    PDF »
The role of a Williams-Beuren syndrome-associated helix-loop-helix domain-containing transcription factor in activin/nodal signaling.
C. Ring, S. Ogata, L. Meek, J. Song, T. Ohta, K. Miyazono, and K. W.Y. Cho (2002)
Genes & Dev. 16, 820-835
   Abstract »    Full Text »    PDF »
Requirement for endoderm and FGF3 in ventral head skeleton formation.
N. B. David, L. Saint-Etienne, M. Tsang, T. F. Schilling, and F. M. Rosa (2002)
Development 129, 4457-4468
   Abstract »    Full Text »    PDF »
Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development.
J. Mathieu, A. Barth, F. M. Rosa, S. W. Wilson, and N. Peyrieras (2002)
Development 129, 3055-3065
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882