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.E mbryonic stem cells (ES cells) are able to form all cell types of the body by following normal embryogenesis (1-3). The pluripotency of ES cells has attracted great attention for their potential use in tissue and cell therapy. However, the molecular and developmental mechanisms controlling pluripotency and differentiation of ES cells are largely unknown, and only a very limited number of genes has so far been shown to affect the fate decisions of inner cell mass (ICM) or ES cells. These genes include Oct4, Fgf4, H2az, Foxd3, Nanog,.Growth factors required for ES cell self-renewal are usually provided by feeder cells, or exogenously (13). Leukemiainhibiting factor (LIF) and its close relatives are the known propluripotency factors for mouse ES cells. It is unclear how many other growth factors or signaling pathways are required for the self-renewal of ES cells. To address these questions, we set out to identify such factors that affect the self-renewal of ES cells. To accomplish this, we isolated and screened sublines of the mouse embryonic fibroblast STO cells for their ability to support the self-renewal of ES cells by using Oct4-GFP as a convenient marker of pluripotency (14-16). By this approach in combination with gene expression profiling, we have identified bone morphogenetic protein 4 (BMP4) as part of the extracellular propluripotency cues. Also, our studies show that BMP4 and LIF have synergistic effect in teratoma formation. Moreover, a number of genes differentially expressed in ES cells cultured with or without exogenous BMP4 have been identified.One of these differentially expressed genes, X-linked inhibitor of apoptosis (Xiap), is expressed at higher levels in ES cells cultured in the presence of exogenous BMP4 than in its absence. XIAP has been implicated in connecting the type I receptors of BMPs and TGF-␤s with the mitogen-activated protein kinase (MAPK) p38 pathway (17)(18)(19)(20). Contrary to previous findings in which BMP signaling up-r...

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