Identification of factors involved in the maintenance of embryonic stem cell self renewal and pluripotency 5

Chapter5

References




183

5 Reference

Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L.
(1997). TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-
Smad4 complex formation and signaling. J Biol Chem 272, 27678-27685.

Ambrosetti, D. C., Basilico, C., and Dailey, L. (1997). Synergistic activation of the
fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein
interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell
Biol 17, 6321-6329.

Attisano, L., Wrana, J. L., Montalvo, E., and Massague, J. (1996). Activation of
signalling by the activin receptor complex. Mol Cell Biol 16, 1066-1073.

Aubert, J., Dunstan, H., Chambers, I., and Smith, A. (2002). Functional gene screening in
embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat
Biotechnol 20, 1240-1245.

Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., and Lovell-Badge, R.

(2003). Multipotent cell lineages in early mouse development depend on SOX2 function.
Genes Dev 17, 126-140.

Bakre, M. M., Hoi, A., Mong, J. C., Koh, Y. Y., Wong, K. Y., and Stanton, L. W. (2007).
Generation of multipotential mesendodermal progenitors from mouse embryonic stem
cells via sustained Wnt pathway activation. J Biol Chem 282, 31703-31712.

Beattie, G. M., Lopez, A. D., Bucay, N., Hinton, A., Firpo, M. T., King, C. C., and Hayek,
A. (2005). Activin A maintains pluripotency of human embryonic stem cells in the
absence of feeder layers. Stem Cells 23, 489-495.

Besser, D. (2004). Expression of nodal, lefty-a, and lefty-B in undifferentiated human
embryonic stem cells requires activation of Smad2/3. J Biol Chem 279, 45076-45084.

Bhattacharya, B., Miura, T., Brandenberger, R., Mejido, J., Luo, Y., Yang, A. X., Joshi,
B. H., Ginis, I., Thies, R. S., Amit, M., et al. (2004). Gene expression in human
embryonic stem cell lines: unique molecular signature. Blood 103, 2956-2964.

Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P.,
Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., et al. (2005). Core
transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947-956.

Brandenberger, R., Khrebtukova, I., Thies, R. S., Miura, T., Jingli, C., Puri, R., Vasicek,
T., Lebkowski, J., and Rao, M. (2004). MPSS profiling of human embryonic stem cells.
BMC Dev Biol 4, 10.

184

Brennan, J., Lu, C. C., Norris, D. P., Rodriguez, T. A., Beddington, R. S., and Robertson,
E. J. (2001). Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411,

965-969.

Brennan, J., Norris, D. P., and Robertson, E. J. (2002). Nodal activity in the node governs
left-right asymmetry. Genes Dev 16, 2339-2344.

Brons IG, Smithers LE, Trotter MW, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM,
Howlett SK, Clarkson A, Ahrlund-Richter L, Pedersen RA, Vallier L. (2007), Derivation
of pluripotent epiblast stem cells from mammalian embryos., Nature 448, 191-195.

Brown, K. A., Pietenpol, J. A., and Moses, H. L. (2007). A tale of two proteins:
differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell
Biochem 101, 9-33.

Burns, C. J., Persaud, S. J., and Jones, P. M. (2006). Diabetes mellitus: a potential target
for stem cell therapy. Curr Stem Cell Res Ther 1, 255-266.

Camus, A., Perea-Gomez, A., Moreau, A., and Collignon, J. (2006). Absence of Nodal
signaling promotes precocious neural differentiation in the mouse embryo. Dev Biol 295,
743-755.

Chambers, I., Colby, D., Robertson, M., Nichols, J., Lee, S., Tweedie, S., and Smith, A.
(2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in
embryonic stem cells. Cell 113, 643-655.

Chambers, I., and Smith, A. (2004). Self-renewal of teratocarcinoma and embryonic stem
cells. Oncogene 23, 7150-7160.

Chen, C., and Shen, M. M. (2004). Two modes by which Lefty proteins inhibit nodal
signaling. Curr Biol 14, 618-624.

Chen, Y., and Schier, A. F. (2001). The zebrafish Nodal signal Squint functions as a
morphogen. Nature 411, 607-610.

Chew, J. L., Loh, Y. H., Zhang, W., Chen, X., Tam, W. L., Yeap, L. S., Li, P., Ang, Y. S.,
Lim, B., Robson, P., and Ng, H. H. (2005). Reciprocal transcriptional regulation of
Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol Cell Biol 25,
6031-6046.

Chu, J., Ding, J., Jeays-Ward, K., Price, S. M., Placzek, M., and Shen, M. M. (2005).
Non-cell-autonomous role for Cripto in axial midline formation during vertebrate
embryogenesis. Development 132, 5539-5551.

Ciardiello, F., Dono, R., Kim, N., Persico, M. G., and Salomon, D. S. (1991a).
Expression of cripto, a novel gene of the epidermal growth factor gene family, leads to in
185

vitro transformation of a normal mouse mammary epithelial cell line. Cancer Res 51,
1051-1054.

Ciardiello, F., Kim, N., Saeki, T., Dono, R., Persico, M. G., Plowman, G. D., Garrigues,
J., Radke, S., Todaro, G. J., and Salomon, D. S. (1991b). Differential expression of
epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci
U S A 88, 7792-7796.

Conlon, F. L., Lyons, K. M., Takaesu, N., Barth, K. S., Kispert, A., Herrmann, B., and
Robertson, E. J. (1994). A primary requirement for nodal in the formation and
maintenance of the primitive streak in the mouse. Development 120, 1919-1928.

Daheron, L., Opitz, S. L., Zaehres, H., Lensch, W. M., Andrews, P. W., Itskovitz-Eldor,
J., and Daley, G. Q. (2004). LIF/STAT3 signaling fails to maintain self-renewal of

human embryonic stem cells. Stem Cells 22, 770-778.

Darr, H., Mayshar, Y., and Benvenisty, N. (2006). Overexpression of NANOG in human
ES cells enables feeder-free growth while inducing primitive ectoderm features.
Development 133, 1193-1201.

Davila, J. C., Cezar, G. G., Thiede, M., Strom, S., Miki, T., and Trosko, J. (2004). Use
and application of stem cells in toxicology. Toxicol Sci 79, 214-223.

Di-Gregorio A, Sancho M, Stuckey DW, Crompton LA, Godwin J, Mishina Y,
Rodriguez TA.(2007) BMP signalling inhibits premature neural differentiation in the
mouse embryo. Development 134, 3359-69

Dunn, N. R., Vincent, S. D., Oxburgh, L., Robertson, E. J., and Bikoff, E. K. (2004).
Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and
patterning in the mouse embryo. Development 131, 1717-1728.

Dvash T, Sharon N, Yanuka O, Benvenisty N. (2007), Molecular analysis of LEFTY-
expressing cells in early human embryoid bodies, Stem Cells. 25, 465-472.

Fan, L., and Collodi, P. (2006). Zebrafish embryonic stem cells. Methods Enzymol 418,
64-77.

Feldman, B., Gates, M. A., Egan, E. S., Dougan, S. T., Rennebeck, G., Sirotkin, H. I.,
Schier, A. F., and Talbot, W. S. (1998). Zebrafish organizer development and germ-layer
formation require nodal-related signals. Nature 395, 181-185.

Fukuda, H., and Takahashi, J. (2005). Embryonic stem cells as a cell source for treating
Parkinson's disease. Expert Opin Biol Ther 5, 1273-1280.

186

Funaba, M., Zimmerman, C. M., and Mathews, L. S. (2002). Modulation of Smad2-
mediated signaling by extracellular signal-regulated kinase. J Biol Chem 277, 41361-
41368.

Gliniak, B. C., McKenna, H. J., Papayannopoulou, T., Thoma, B., and et al. (1995).
Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes
placental, skeletal, neural and metabolic defects and results in perinatal death.
Development 121, 1283-1299.

Goldin, S. N., and Papaioannou, V. E. (2003). Paracrine action of FGF4 during
periimplantation development maintains trophectoderm and primitive endoderm. Genesis
36, 40-47.

Gu, Z., Nomura, M., Simpson, B. B., Lei, H., Feijen, A., van den Eijnden-van Raaij, J.,
Donahoe, P. K., and Li, E. (1998). The type I activin receptor ActRIB is required for egg
cylinder organization and gastrulation in the mouse. Genes Dev 12, 844-857.

Hamada, H., Meno, C., Watanabe, D., and Saijoh, Y. (2002). Establishment of vertebrate
left-right asymmetry. Nat Rev Genet 3, 103-113.

Hamatani, T., Carter, M. G., Sharov, A. A., and Ko, M. S. (2004). Dynamics of global
gene expression changes during mouse preimplantation development. Dev Cell 6, 117-
131.

Harms, P. W., and Chang, C. (2003). Tomoregulin-1 (TMEFF1) inhibits nodal signaling
through direct binding to the nodal coreceptor Cripto. Genes Dev 17, 2624-2629.

Hendrix, M. J., Seftor, E. A., Seftor, R. E., Kasemeier-Kulesa, J., Kulesa, P. M., and

Postovit, L. M. (2007). Reprogramming metastatic tumour cells with embryonic
microenvironments. Nat Rev Cancer 7, 246-255.

Hirano, T., Ishihara, K., and Hibi, M. (2000). Roles of STAT3 in mediating the cell
growth, differentiation and survival signals relayed through the IL-6 family of cytokine
receptors. Oncogene 19, 2548-2556.

Ho, H. Y., and Li, M. (2006). Potential application of embryonic stem cells in Parkinson's
disease: drug screening and cell therapy. Regen Med 1, 175-182.

Iannaccone, P. M., Taborn, G. U., Garton, R. L., Caplice, M. D., and Brenin, D. R.
(1994). Pluripotent embryonic stem cells from the rat are capable of producing chimeras.
Dev Biol 163, 288-292.

Inman, G. J., Nicolas, F. J., Callahan, J. F., Harling, J. D., Gaster, L. M., Reith, A. D.,
Laping, N. J., and Hill, C. S. (2002). 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. Mol Pharmacol 62, 65-74.
187


James, D., Levine, A. J., Besser, D., and Hemmati-Brivanlou, A. (2005).
TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in
human embryonic stem cells. Development 132, 1273-1282.

Jiang J, Chan YS, Loh YH, Cai J, Tong GQ, Lim CA, Robson P, Zhong S, Ng HH.(2008),
A core Klf circuitry regulates self-renewal of embryonic stem cells, Nat Cell Biol. 10,
353-360.

Jinnin, M., Ihn, H., and Tamaki, K. (2006). Characterization of SIS3, a novel specific

inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced
extracellular matrix expression. Mol Pharmacol 69, 597-607.

Jornvall, H., Reissmann, E., Andersson, O., Mehrkash, M., and Ibanez, C. F. (2004).
ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in
the mouse. Mol Cell Biol 24, 9383-9389.

Kitamura, R., Takahashi, T., Nakajima, N., Isodono, K., Asada, S., Ueno, H., Ueyama, T.,
Yoshikawa, T., Matsubara, H., and Oh, H. (2007). Stage-specific role of endogenous
Smad2 activation in cardiomyogenesis of embryonic stem cells. Circ Res 101, 78-87.

Larsson, J., Goumans, M. J., Sjostrand, L. J., van Rooijen, M. A., Ward, D., Leveen, P.,
Xu, X., ten Dijke, P., Mummery, C. L., and Karlsson, S. (2001). Abnormal angiogenesis
but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. Embo J 20,
1663-1673.

Levine, A. J., and Brivanlou, A. H. (2006). GDF3, a BMP inhibitor, regulates cell fate in
stem cells and early embryos. Development 133, 209-216.

Li, J., Pan, G., Cui, K., Liu, Y., Xu, S., and Pei, D. (2007). A dominant-negative form of
mouse SOX2 induces trophectoderm differentiation and progressive polyploidy in mouse
embryonic stem cells. J Biol Chem 282, 19481-19492.

Li, M., Sendtner, M., and Smith, A. (1995). Essential function of LIF receptor in motor
neurons. Nature 378, 724-727.

Li, Y., McClintick, J., Zhong, L., Edenberg, H. J., Yoder, M. C., and Chan, R. J. (2005).
Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the
zinc finger transcription factor Klf4. Blood 105, 635-637.

Loh, Y. H., Wu, Q., Chew, J. L., Vega, V. B., Zhang, W., Chen, X., Bourque, G., George,
J., Leong, B., Liu, J., et al. (2006). The Oct4 and Nanog transcription network regulates
pluripotency in mouse embryonic stem cells. Nat Genet 38, 431-440.

Lowe, L. A., Yamada, S., and Kuehn, M. R. (2001). Genetic dissection of nodal function
in patterning the mouse embryo. Development 128, 1831-1843.
188


Lu, C. C., and Robertson, E. J. (2004). Multiple roles for Nodal in the epiblast of the
mouse embryo in the establishment of anterior-posterior patterning. Dev Biol 273, 149-
159.

Matin, M. M., Walsh, J. R., Gokhale, P. J., Draper, J. S., Bahrami, A. R., Morton, I.,
Moore, H. D., and Andrews, P. W. (2004). Specific knockdown of Oct4 and beta2-
microglobulin expression by RNA interference in human embryonic stem cells and
embryonic carcinoma cells. Stem Cells 22, 659-668.

Matsuda, T., Nakamura, T., Nakao, K., Arai, T., Katsuki, M., Heike, T., and Yokota, T.
(1999). STAT3 activation is sufficient to maintain an undifferentiated state of mouse
embryonic stem cells. Embo J 18, 4261-4269.

Mee, P. J., O'Brien, C. M., Thomson, H., van der Sar, S., Lakics, V., and Allsopp, T. E.
(2006). Embryonic stem cells as a source of differentiated neural cells for
pharmacological screens. Methods Mol Biol 329, 353-369.

Meno, C., Gritsman, K., Ohishi, S., Ohfuji, Y., Heckscher, E., Mochida, K., Shimono, A.,
Kondoh, H., Talbot, W. S., Robertson, E. J., et al. (1999). Mouse Lefty2 and zebrafish
antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol Cell
4, 287-298.

Meno, C., Ito, Y., Saijoh, Y., Matsuda, Y., Tashiro, K., Kuhara, S., and Hamada, H.
(1997). Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2:
their distinct expression domains, chromosomal linkage and direct neuralizing activity in
Xenopus embryos. Genes Cells 2, 513-524.

Meno, C., Saijoh, Y., Fujii, H., Ikeda, M., Yokoyama, T., Yokoyama, M., Toyoda, Y.,
and Hamada, H. (1996). Left-right asymmetric expression of the TGF beta-family
member lefty in mouse embryos. Nature 381, 151-155.

Mitsui, K., Tokuzawa, Y., Itoh, H., Segawa, K., Murakami, M., Takahashi, K.,
Maruyama, M., Maeda, M., and Yamanaka, S. (2003). The homeoprotein Nanog is
required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113, 631-
642.

Moffat, J., and Sabatini, D. M. (2006). Building mammalian signalling pathways with
RNAi screens. Nat Rev Mol Cell Biol 7, 177-187.

Molofsky, A. V., Pardal, R., and Morrison, S. J. (2004). Diverse mechanisms regulate
stem cell self-renewal. Curr Opin Cell Biol 16, 700-707.

Nakatake, Y., Fukui, N., Iwamatsu, Y., Masui, S., Takahashi, K., Yagi, R., Yagi, K.,
Miyazaki, J., Matoba, R., Ko, M. S., and Niwa, H. (2006). Klf4 cooperates with Oct3/4
189

and Sox2 to activate the Lefty1 core promoter in embryonic stem cells. Mol Cell Biol 26,
7772-7782.

Nichols, J., Chambers, I., Taga, T., and Smith, A. (2001). Physiological rationale for
responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 128,

2333-2339.

Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I.,
Scholer, H., and Smith, A. (1998). Formation of pluripotent stem cells in the mammalian
embryo depends on the POU transcription factor Oct4. Cell 95, 379-391.

Niwa, H., Burdon, T., Chambers, I., and Smith, A. (1998). Self-renewal of pluripotent
embryonic stem cells is mediated via activation of STAT3. Genes Dev 12, 2048-2060.

Niwa, H., Miyazaki, J., and Smith, A. G. (2000). Quantitative expression of Oct-3/4
defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24, 372-
376.

Nomura, M., and Li, E. (1998). Smad2 role in mesoderm formation, left-right patterning
and craniofacial development. Nature 393, 786-790.

Ogawa, K., Saito, A., Matsui, H., Suzuki, H., Ohtsuka, S., Shimosato, D., Morishita, Y.,
Watabe, T., Niwa, H., and Miyazono, K. (2007). Activin-Nodal signaling is involved in
propagation of mouse embryonic stem cells. J Cell Sci 120, 55-65.

Oh, S. P., and Li, E. (1997). The signaling pathway mediated by the type IIB activin
receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11,
1812-1826.
Pease, S., and Williams, R. L. (1990). Formation of germ-line chimeras from embryonic
stem cells maintained with recombinant leukemia inhibitory factor. Exp Cell Res 190,
209-211.

Pera, M. F., Andrade, J., Houssami, S., Reubinoff, B., Trounson, A., Stanley, E. G.,
Ward-van Oostwaard, D., and Mummery, C. (2004). Regulation of human embryonic
stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci 117, 1269-1280.

Perea-Gomez, A., Vella, F. D., Shawlot, W., Oulad-Abdelghani, M., Chazaud, C., Meno,
C., Pfister, V., Chen, L., Robertson, E., Hamada, H., et al. (2002). Nodal antagonists in
the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev
Cell 3, 745-756.

Pesce, M., and Scholer, H. R. (2001). Oct-4: gatekeeper in the beginnings of mammalian
development. Stem Cells 19, 271-278.

Postovit, L. M., Seftor, E. A., Seftor, R. E., and Hendrix, M. J. (2007). Targeting Nodal
in malignant melanoma cells. Expert Opin Ther Targets 11, 497-505.
190


Pouton, C. W., and Haynes, J. M. (2007). Embryonic stem cells as a source of models for
drug discovery. Nat Rev Drug Discov 6, 605-616.

Rao, M. (2004). Conserved and divergent paths that regulate self-renewal in mouse and
human embryonic stem cells. Dev Biol 275, 269-286.

Raz, R., Lee, C. K., Cannizzaro, L. A., d'Eustachio, P., and Levy, D. E. (1999). Essential
role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A 96, 2846-
2851.

Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A., and Bongso, A. (2000).
Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat
Biotechnol 18, 399-404.

Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A. (2004) Rational
siRNA design for RNA interference. Nat Biotechnol. 22,326–330 .

Rodda, D. J., Chew, J. L., Lim, L. H., Loh, Y. H., Wang, B., Ng, H. H., and Robson, P.
(2005). Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280,
24731-24737.

Rodriguez, R. T., Velkey, J. M., Lutzko, C., Seerke, R., Kohn, D. B., O'Shea, K. S., and
Firpo, M. T. (2007). Manipulation of OCT4 levels in human embryonic stem cells results
in induction of differential cell types. Exp Biol Med (Maywood) 232, 1368-1380.

Ross S, Cheung E, Petrakis TG, Howell M, Kraus WL, Hill CS. (2006) Smads
orchestrate specific histone modifications and chromatin remodeling to activate
transcription. EMBO J. 4, 490-502.

Saijoh, Y., Adachi, H., Mochida, K., Ohishi, S., Hirao, A., and Hamada, H. (1999).
Distinct transcriptional regulatory mechanisms underlie left-right asymmetric expression
of lefty-1 and lefty-2. Genes Dev 13, 259-269.

Saijoh, Y., Adachi, H., Sakuma, R., Yeo, C. Y., Yashiro, K., Watanabe, M., Hashiguchi,
H., Mochida, K., Ohishi, S., Kawabata, M., et al. (2000). Left-right asymmetric
expression of lefty2 and nodal is induced by a signaling pathway that includes the
transcription factor FAST2. Mol Cell 5, 35-47.

Sakuma, R., Ohnishi Yi, Y., Meno, C., Fujii, H., Juan, H., Takeuchi, J., Ogura, T., Li, E.,
Miyazono, K., and Hamada, H. (2002). Inhibition of Nodal signalling by Lefty mediated
through interaction with common receptors and efficient diffusion. Genes Cells 7, 401-
412.

Saloman, D. S., Bianco, C., Ebert, A. D., Khan, N. I., De Santis, M., Normanno, N.,
Wechselberger, C., Seno, M., Williams, K., Sanicola, M., et al. (2000). The EGF-CFC
191

family: novel epidermal growth factor-related proteins in development and cancer.
Endocr Relat Cancer 7, 199-226.

Sampath, K., Rubinstein, A. L., Cheng, A. M., Liang, J. O., Fekany, K., Solnica-Krezel,
L., Korzh, V., Halpern, M. E., and Wright, C. V. (1998). Induction of the zebrafish
ventral brain and floorplate requires cyclops/nodal signalling. Nature 395, 185-189.

Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., and Brivanlou, A. H. (2004).
Maintenance of pluripotency in human and mouse embryonic stem cells through
activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10,
55-63.

Schier, A. F., and Shen, M. M. (2000). Nodal signalling in vertebrate development.
Nature 403, 385-389.

Seiler, A. E., Buesen, R., Visan, A., and Spielmann, H. (2006). Use of murine embryonic
stem cells in embryotoxicity assays: the embryonic stem cell test. Methods Mol Biol 329,
371-395.

Shen, M. M. (2007). Nodal signaling: developmental roles and regulation. Development
134, 1023-1034.

Shi, W., Wang, H., Pan, G., Geng, Y., Guo, Y., and Pei, D. (2006). Regulation of the
pluripotency marker Rex-1 by Nanog and Sox2. J Biol Chem 281, 23319-23325.

Shiratori, H., Sakuma, R., Watanabe, M., Hashiguchi, H., Mochida, K., Sakai, Y.,
Nishino, J., Saijoh, Y., Whitman, M., and Hamada, H. (2001). Two-step regulation of
left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance
by Nkx2. Mol Cell 7, 137-149.

Smith, A. G., Heath, J. K., Donaldson, D. D., Wong, G. G., Moreau, J., Stahl, M., and
Rogers, D. (1988). Inhibition of pluripotential embryonic stem cell differentiation by
purified polypeptides. Nature 336, 688-690.

Smith, A. G., and Hooper, M. L. (1987). Buffalo rat liver cells produce a diffusible
activity which inhibits the differentiation of murine embryonal carcinoma and embryonic
stem cells. Dev Biol 121, 1-9.

Smith JR, Vallier L, Lupo G, Alexander M, Harris WA, Pedersen RA (2008), Inhibition
of Activin/Nodal signaling promotes specification of human embryonic stem cells into
neuroectoderm, Dev Biol. 313, 107-117.

Stewart, C. L., Kaspar, P., Brunet, L. J., Bhatt, H., Gadi, I., Kontgen, F., and Abbondanzo,
S. J. (1992). Blastocyst implantation depends on maternal expression of leukaemia
inhibitory factor. Nature 359, 76-79.

192

Tabibzadeh, S., and Hemmati-Brivanlou, A. (2006). Lefty at the crossroads of "stemness"
and differentiative events. Stem Cells 24, 1998-2006.

Takagi, Y., Takahashi, J., Saiki, H., Morizane, A., Hayashi, T., Kishi, Y., Fukuda, H.,
Okamoto, Y., Koyanagi, M., Ideguchi, M., et al. (2005). Dopaminergic neurons
generated from monkey embryonic stem cells function in a Parkinson primate model. J
Clin Invest 115, 102-109.

Takahashi K, Yamanaka S. (2006), Induction of pluripotent stem cells from mouse
embryonic and adult fibroblast cultures by defined factors., Cell. 126(4), 663-76.

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka

S.(2007), Induction of pluripotent stem cells from adult human fibroblasts by defined
factors, Cell.131(5), 861-72.

Takenaga, M., Fukumoto, M., and Hori, Y. (2007). Regulated Nodal signaling promotes
differentiation of the definitive endoderm and mesoderm from ES cells. J Cell Sci 120,
2078-2090.

Tesar, P. J. (2005). Derivation of germ-line-competent embryonic stem cell lines from
preblastocyst mouse embryos. Proc Natl Acad Sci U S A 102, 8239-8244.

Tesar PJ, Chenoweth JG, Brook FA, Davies TJ, Evans EP, Mack DL, Gardner RL,
McKay RD (2007), New cell lines from mouse epiblast share defining features with
human embryonic stem cells, Nature. 448, 196-199.

Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J.,
Marshall, V. S., and Jones, J. M. (1998). Embryonic stem cell lines derived from human
blastocysts. Science 282, 1145-1147.

Thomson, J. A., and Marshall, V. S. (1998). Primate embryonic stem cells. Curr Top Dev
Biol 38, 133-165.

Topczewska, J. M., Postovit, L. M., Margaryan, N. V., Sam, A., Hess, A. R., Wheaton,
W. W., Nickoloff, B. J., Topczewski, J., and Hendrix, M. J. (2006). Embryonic and
tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness.
Nat Med 12, 925-932.

Ulloa, L., Creemers, J. W., Roy, S., Liu, S., Mason, J., and Tabibzadeh, S. (2001). Lefty
proteins exhibit unique processing and activate the MAPK pathway. J Biol Chem 276,
21387-21396.

Ulloa, L., and Tabibzadeh, S. (2001). Lefty inhibits receptor-regulated Smad
phosphorylation induced by the activated transforming growth factor-beta receptor. J Biol
Chem 276, 21397-21404.

193

Vackova, I., Ungrova, A., and Lopes, F. (2007). Putative embryonic stem cell lines from
pig embryos. J Reprod Dev 53, 1137-1149.

Vallier, L., Alexander, M., and Pedersen, R. A. (2005). Activin/Nodal and FGF pathways
cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118, 4495-
4509.

Vallier, L., Reynolds, D., and Pedersen, R. A. (2004). Nodal inhibits differentiation of
human embryonic stem cells along the neuroectodermal default pathway. Dev Biol 275,
403-421.

Varga, A. C., and Wrana, J. L. (2005). The disparate role of BMP in stem cell biology.
Oncogene 24, 5713-5721.

Voss, A. K., Thomas, T., and Gruss, P. (1997). Germ line chimeras from female ES cells.
Exp Cell Res 230, 45-49.


Wei, C. L., Miura, T., Robson, P., Lim, S. K., Xu, X. Q., Lee, M. Y., Gupta, S., Stanton,
L., Luo, Y., Schmitt, J., et al. (2005). Transcriptome profiling of human and murine ESCs
identifies divergent paths required to maintain the stem cell state. Stem Cells 23, 166-185.

Wieduwilt Matthew J., (2003). SMAD3 in embryonic patterning, mesoderm induction
and colorectal cancer induction in the mouse, University of Texas Southwestern Medical

Center, phD dissertation

Wolf, E., Kramer, R., Polejaeva, I., Thoenen, H., and Brem, G. (1994). Efficient
generation of chimaeric mice using embryonic stem cells after long-term culture in the
presence of ciliary neurotrophic factor. Transgenic Res 3, 152-158.

Xiao, L., Yuan, X., and Sharkis, S. J. (2006). Activin A maintains self-renewal and
regulates fibroblast growth factor, Wnt, and bone morphogenic protein pathways in
human embryonic stem cells. Stem Cells 24, 1476-1486.

Xu, R. H., Chen, X., Li, D. S., Li, R., Addicks, G. C., Glennon, C., Zwaka, T. P., and
Thomson, J. A. (2002). BMP4 initiates human embryonic stem cell differentiation to
trophoblast. Nat Biotechnol 20, 1261-1264.

Xu, R. H., Peck, R. M., Li, D. S., Feng, X., Ludwig, T., and Thomson, J. A. (2005). Basic
FGF and suppression of BMP signaling sustain undifferentiated proliferation of human
ES cells. Nat Methods 2, 185-190.

Yamamoto, H., Quinn, G., Asari, A., Yamanokuchi, H., Teratani, T., Terada, M., and
Ochiya, T. (2003). Differentiation of embryonic stem cells into hepatocytes: biological
functions and therapeutic application. Hepatology 37, 983-993.

194

Yamamoto, M., Meno, C., Sakai, Y., Shiratori, H., Mochida, K., Ikawa, Y., Saijoh, Y.,
and Hamada, H. (2001). The transcription factor FoxH1 (FAST) mediates Nodal
signaling during anterior-posterior patterning and node formation in the mouse. Genes
Dev 15, 1242-1256.

Yan, Y. T., Gritsman, K., Ding, J., Burdine, R. D., Corrales, J. D., Price, S. M., Talbot, W.

S., Schier, A. F., and Shen, M. M. (1999). Conserved requirement for EGF-CFC genes in
vertebrate left-right axis formation. Genes Dev 13, 2527-2537.

Yang, X., Li, C., Xu, X., and Deng, C. (1998). The tumor suppressor SMAD4/DPC4 is
essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci U
S A 95, 3667-3672.

Ying, Q. L., Nichols, J., Chambers, I., and Smith, A. (2003). BMP induction of Id
proteins suppresses differentiation and sustains embryonic stem cell self-renewal in
collaboration with STAT3. Cell 115, 281-292.

Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J,
Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. (2007), Induced pluripotent
stem cell lines derived from human somatic cells., Science. 318, 1917-1920.

Zeineddine, D., Papadimou, E., Chebli, K., Gineste, M., Liu, J., Grey, C., Thurig, S.,
Behfar, A., Wallace, V. A., Skerjanc, I. S., and Puceat, M. (2006). Oct-3/4 dose
dependently regulates specification of embryonic stem cells toward a cardiac lineage and
early heart development. Dev Cell 11, 535-546.

Zhang, J., Tam, W. L., Tong, G. Q., Wu, Q., Chan, H. Y., Soh, B. S., Lou, Y., Yang, J.,
Ma, Y., Chai, L., et al. (2006). Sall4 modulates embryonic stem cell pluripotency and
early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8,
1114-1123.

Zhang, J. G., Owczarek, C. M., Ward, L. D., Howlett, G. J., Fabri, L. J., Roberts, B. A.,
and Nicola, N. A. (1997). Evidence for the formation of a heterotrimeric complex of
leukaemia inhibitory factor with its receptor subunits in solution. Biochem J 325 ( Pt 3),
693-700.