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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Version of Record online: 21 MAR 2011
Copyright © 2011 AlphaMed Press
Volume 29, Issue 3, pages 474–485, March 2011
How to Cite
Casanova, E. A., Shakhova, O., Patel, S. S., Asner, I. N., Pelczar, P., Weber, F. A., Graf, U., Sommer, L., Bürki, K. and Cinelli, P. (2011), Pramel7 Mediates LIF/STAT3-Dependent Self-Renewal in embryoniC Stem Cells. STEM CELLS, 29: 474–485. doi: 10.1002/stem.588
Disclosure of potential conflicts of interest is found at the end of this article.
Author contributions: E.A.C.: performed the experiments, wrote the manuscript; O.S.: performed the experiments, edited the manuscript; I.N.A., S.S.P, F.A.W., and U.G.: contributed in performing the experiments; L.S.: supervised the project, edited the manuscript; K.B.: supervised the project, edited the manuscript; P.C.: designed all experiments, supervised the project, wrote the manuscript.
First published online in STEM CELLSEXPRESS December 23, 2010.
- Issue online: 21 MAR 2011
- Version of Record online: 21 MAR 2011
- Accepted manuscript online: 23 DEC 2010 01:51PM EST
- Manuscript Accepted: 13 DEC 2010
- Manuscript Received: 28 OCT 2010
- Embryonic stem cells;
A unique and complex signaling network allows ESCs to undergo extended proliferation in vitro, while maintaining their capacity for multilineage differentiation. Genuine ESC identity can only be maintained when both self-renewal and suppression of differentiation are active and balanced. Here, we identify Pramel7 (preferentially expressed antigen in melanoma-like 7) as a novel factor crucial for maintenance of pluripotency and leukemia inhibitory factor (LIF)-mediated self-renewal in ESCs. In vivo, Pramel7 expression was exclusively found in the pluripotent pools of cells, namely, the central part of the morula and the inner cell mass of the blastocyst. Ablation of Pramel7 induced ESC differentiation, whereas its overexpression was sufficient to support long-term self-renewal in the absence of exogenous LIF. Furthermore, Pramel7 overexpression suppressed differentiation in ESCs in vitro and in vivo. This process was reversible, as on transgene excision cells reverted to a LIF-dependent state and regained their capacity to participate in the formation of chimeric mice. Molecularly, LIF directly controls Pramel7 expression, involving both STAT3-dependent transcriptional regulation and PI3K-dependent phosphorylation of glycogen synthase kinase 3β. Pramel7 expression in turn confers constitutive self-renewal and prevents differentiation through inactivation of extracellular signal-regulated kinase phosphorylation. Accordingly, knockdown of Pramel7 promotes ESC differentiation in presence of LIF and even on forced STAT3-activation. Thus, Pramel7 represents a central and essential factor in the signaling network regulating pluripotency and self-renewal in ESCs. STEM CELLS 2011;29:474–485