Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells.
ES cells represent a valuable model for investigating early embryo development and hold promise for future regenerative medicine strategies. The self-renewal of pluripotent mouse ES cells has been shown to require extrinsic stimulation by the bone morphogenetic protein (BMP) and leukemia inhibitory factor signaling pathways and the expression of the transcription factors Oct4 and Nanog. However, the network of interactions among extrinsic and intrinsic determinants of ES cell pluripotency is currently poorly understood. Here, we show that Nanog expression is up-regulated in mouse ES cells by the binding of T (Brachyury) and STAT3 to an enhancer element in the mouse Nanog gene. We further show that Nanog blocks BMP-induced mesoderm differentiation of ES cells by physically interacting with Smad1 and interfering with the recruitment of coactivators to the active Smad transcriptional complexes. Taken together, our findings illustrate the existence of ES cell-specific regulatory networks that underlie the maintenance of ES cell pluripotency and provide mechanistic insights into the role of Nanog in this process.
Suzuki
Atsushi
A
*Gene Expression Laboratory.|Stem Cell Research Center, and.
Raya
Ángel
Á
*Gene Expression Laboratory.|Stem Cell Research Center, and.|Institució Catalana de Recerca i Estudis Avançats and Center of Regenerative Medicine, Dr. Aiguader 80, 08003 Barcelona, Spain; and.
Kawakami
Yasuhiko
Y
*Gene Expression Laboratory.
Morita
Masanobu
M
*Gene Expression Laboratory.|Stem Cell Research Center, and.
Matsui
Takaaki
T
*Gene Expression Laboratory.
Nakashima
Kinichi
K
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037.|**Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101, Japan.
Gage
Fred H
FH
Stem Cell Research Center, and.|Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037.
Rodríguez-Esteban
Concepción
C
*Gene Expression Laboratory.
Izpisúa Belmonte
Juan Carlos
JC
*Gene Expression Laboratory, belmonte@salk.edu.|Stem Cell Research Center, and.|Institució Catalana de Recerca i Estudis Avançats and Center of Regenerative Medicine, Dr. Aiguader 80, 08003 Barcelona, Spain; and.
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology*; D004742:Enhancer Elements, Genetic; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D000071317:Nanog Homeobox Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D000098908:Brachyury Protein
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050791:STAT Transcription Factors; D051898:Smad1 Protein; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C475540:Nanog protein, mouse; C497401:Smad1 protein, mouse