|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 9 February 2005
doi: 10.1242/dev.01706
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
* Author for correspondence (e-mail: brvnlou{at}mail.rockefeller.edu)
Accepted 18 January 2005
Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFß superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFß/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFß/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFß signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFß and WNT signaling in these contexts.
Key words: TGFß signaling, Human embryonic stem cells (hESCs), SMAD2/3
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  A. F. Schier Nodal Morphogens Cold Spring Harb Perspect Biol, November 1, 2009; 1(5): a003459 - a003459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Di Pasquale and A. H. Brivanlou Bone Morphogenetic Protein 15 (BMP15) Acts as a BMP and Wnt Inhibitor during Early Embryogenesis J. Biol. Chem., September 18, 2009; 284(38): 26127 - 26136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Xia and A. L Schneyer The biology of activin: recent advances in structure, regulation and function J. Endocrinol., July 1, 2009; 202(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-F. Chen, C.-Y. Chuang, Y.-K. Shieh, H.-W. Chang, H.-N. Ho, and H.-C. Kuo Novel autogenic feeders derived from human embryonic stem cells (hESCs) support an undifferentiated status of hESCs in xeno-free culture conditions Hum. Reprod., May 1, 2009; 24(5): 1114 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Vallier, S. Mendjan, S. Brown, Z. Chng, A. Teo, L. E. Smithers, M. W. B. Trotter, C. H.-H. Cho, A. Martinez, P. Rugg-Gunn, et al. Activin/Nodal signalling maintains pluripotency by controlling Nanog expression Development, April 15, 2009; 136(8): 1339 - 1349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Swaney, C. D. Wenger, J. A. Thomson, and J. J. Coon Human embryonic stem cell phosphoproteome revealed by electron transfer dissociation tandem mass spectrometry PNAS, January 27, 2009; 106(4): 995 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wang, Y. Shen, X. Yuan, K. Chen, X. Guo, Y. Chen, Y. Niu, J. Li, R.-H. Xu, X. Yan, et al. Dissecting Signaling Pathways That Govern Self-renewal of Rabbit Embryonic Stem Cells J. Biol. Chem., December 19, 2008; 283(51): 35929 - 35940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nagaoka, Y. Hagiwara, K. Takemura, Y. Murakami, J. Li, S. A. Duncan, and T. Akaike Design of the Artificial Acellular Feeder Layer for the Efficient Propagation of Mouse Embryonic Stem Cells J. Biol. Chem., September 26, 2008; 283(39): 26468 - 26476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Furue, J. Na, J. P. Jackson, T. Okamoto, M. Jones, D. Baker, R.-I. Hata, H. D. Moore, J. D. Sato, and P. W. Andrews Heparin promotes the growth of human embryonic stem cells in a defined serum-free medium PNAS, September 9, 2008; 105(36): 13409 - 13414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wu, W. Zhang, G. Chen, L. Cheng, J. Liao, N. Jia, Y. Gao, H. Dai, J. Yuan, L. Cheng, et al. Combinatorial Signals of Activin/Nodal and Bone Morphogenic Protein Regulate the Early Lineage Segregation of Human Embryonic Stem Cells J. Biol. Chem., September 5, 2008; 283(36): 24991 - 25002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Meng, X. Cheng, L. Yang, N. Hou, X. Yang, and A. Meng Accelerated re-epithelialization in Dpr2-deficient mice is associated with enhanced response to TGF{beta} signaling J. Cell Sci., September 1, 2008; 121(17): 2904 - 2912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sumi, N. Tsuneyoshi, N. Nakatsuji, and H. Suemori Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/{beta}-catenin, Activin/Nodal and BMP signaling Development, September 1, 2008; 135(17): 2969 - 2979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yu and J. A. Thomson Pluripotent stem cell lines Genes & Dev., August 1, 2008; 22(15): 1987 - 1997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-M. Postovit, N. V. Margaryan, E. A. Seftor, D. A. Kirschmann, A. Lipavsky, W. W. Wheaton, D. E. Abbott, R. E. B. Seftor, and M. J. C. Hendrix Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells PNAS, March 18, 2008; 105(11): 4329 - 4334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Zhu, J. Q. Boone, P. A. Jensen, S. Hanna, L. Podemski, J. Locke, C. Q. Doe, and M. B. O'Connor Drosophila Activin- and the Activin-like product Dawdle function redundantly to regulate proliferation in the larval brain Development, February 1, 2008; 135(3): 513 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, T. C. Schulz, E. S. Sherrer, D. S. Dauphin, S. Shin, A. M. Nelson, C. B. Ware, M. Zhan, C.-Z. Song, X. Chen, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling Blood, December 1, 2007; 110(12): 4111 - 4119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Emami and M. A. S. Chaudhry Self-renewal and Proliferation of Murine Embryonic Stem Cells: A Study of Glycosaminoglycans Effect on Feeder-Free Cultures Journal of Bioactive and Compatible Polymers, May 1, 2007; 22(3): 314 - 322. [Abstract] [PDF]
|
|
|
|
|
|
M. M. Shen Nodal signaling: developmental roles and regulation Development, March 15, 2007; 134(6): 1023 - 1034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Allegrucci and L.E. Young Differences between human embryonic stem cell lines Hum. Reprod. Update, March 1, 2007; 13(2): 103 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ogawa, A. Saito, H. Matsui, H. Suzuki, S. Ohtsuka, D. Shimosato, Y. Morishita, T. Watabe, H. Niwa, and K. Miyazono Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells J. Cell Sci., January 1, 2007; 120(1): 55 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Steiner, M. J. Engleka, Q. Lu, E. C. Piwarzyk, S. Yaklichkin, J. L. Lefebvre, J. W. Walters, L. Pineda-Salgado, P. A. Labosky, and D. S. Kessler FoxD3 regulation of Nodal in the Spemann organizer is essential for Xenopus dorsal mesoderm development Development, December 15, 2006; 133(24): 4827 - 4838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakatake, N. Fukui, Y. Iwamatsu, S. Masui, K. Takahashi, R. Yagi, K. Yagi, J.-i. Miyazaki, R. Matoba, M. S. H. Ko, et al. Klf4 Cooperates with Oct3/4 and Sox2 To Activate the Lefty1 Core Promoter in Embryonic Stem Cells Mol. Cell. Biol., October 15, 2006; 26(20): 7772 - 7782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bibikova, E. Chudin, B. Wu, L. Zhou, E. W. Garcia, Y. Liu, S. Shin, T. W. Plaia, J. M. Auerbach, D. E. Arking, et al. Human embryonic stem cells have a unique epigenetic signature Genome Res., September 1, 2006; 16(9): 1075 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-y. Yasuda, N. Tsuneyoshi, T. Sumi, K. Hasegawa, T. Tada, N. Nakatsuji, and H. Suemori NANOG maintains self-renewal of primate ES cells in the absence of a feeder layer. Genes Cells, September 1, 2006; 11(9): 1115 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Knockaert, G. Sapkota, C. Alarcon, J. Massague, and A. H. Brivanlou Unique players in the BMP pathway: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling PNAS, August 8, 2006; 103(32): 11940 - 11945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mesnard, M. Guzman-Ayala, and D. B. Constam Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning Development, July 1, 2006; 133(13): 2497 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yao, S. Chen, J. Clark, E. Hao, G. M. Beattie, A. Hayek, and S. Ding Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions PNAS, May 2, 2006; 103(18): 6907 - 6912. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-G. Chen, Q. Wang, S.-L. Lin, C. D. Chang, J. Chung, and S.-Y. Ying Activin Signaling and Its Role in Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis. Experimental Biology and Medicine, May 1, 2006; 231(5): 534 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Poon, F. Clermont, M. T. Firpo, and R. J. Akhurst TGF{beta} inhibition of yolk-sac-like differentiation of human embryonic stem-cell-derived embryoid bodies illustrates differences between early mouse and human development J. Cell Sci., February 15, 2006; 119(4): 759 - 768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Rho, K. Yu, J.-S. Han, J.-I. Chae, D.-B. Koo, H.-S. Yoon, S.-Y. Moon, K.-K. Lee, and Y.-M. Han Transcriptional profiling of the developmentally important signalling pathways in human embryonic stem cells Hum. Reprod., February 1, 2006; 21(2): 405 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chen, S. M. Ware, A. Sato, D. E. Houston-Hawkins, R. Habas, M. M. Matzuk, M. M. Shen, and C. W. Brown The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo Development, January 15, 2006; 133(2): 319 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Vallier, M. Alexander, and R. A. Pedersen Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells J. Cell Sci., October 1, 2005; 118(19): 4495 - 4509. [Abstract] [Full Text] [PDF]
|
|
