title: BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways.
abstract: The fate of pluripotent stem cells is tightly controlled during early embryonic development. Both the derivation and the maintenance of embryonic stem cells (ES cells) in vitro depend on feeder cell-derived growth factors that are largely unidentified. To dissect the mechanisms governing pluripotency, we conducted a screen to identify factors that are produced by mouse embryonic fibroblast STO cells and are required to maintain the pluripotency of ES cells. One of the factors is bone morphogenetic protein 4 (BMP4). Unexpectedly, the major effect of BMP4 on the self-renewal of ES cells is accomplished by means of the inhibition of both extracellular receptor kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) pathways, and inhibitors of ERK and p38 MAPKs mimic the effect of BMP4 on ES cells. Importantly, inhibition of the p38 MAPK pathway by SB203580 overcomes the block in deriving ES cells from blastocysts lacking a functional Alk3, the BMP type IA receptor. These results uncover a paradigm for BMP signaling in the biology of pluripotent stem cells.
authors.affiliation: Cecil H. and Ida Green Center for Reproductive Biology Sciences and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qi
authors.forename: Teng-Guo
authors.initials: TG
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Holly
authors.initials: H
authors.lastname: Simmons
authors.forename: Shigeto
authors.initials: S
authors.lastname: Miura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Guang-Quan
authors.initials: GQ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein