title: Pramel7 mediates LIF/STAT3-dependent self-renewal in embryonic stem cells.
abstract: 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.
authors.affiliation: Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Casanova
authors.forename: Olga
authors.initials: O
authors.lastname: Shakhova
authors.forename: Sameera S
authors.initials: SS
authors.lastname: Patel
authors.forename: Igor N
authors.initials: IN
authors.lastname: Asner
authors.forename: Pawel
authors.initials: P
authors.lastname: Pelczar
authors.forename: Fabienne A
authors.initials: FA
authors.lastname: Weber
authors.forename: Urs
authors.initials: U
authors.lastname: Graf
authors.forename: Lukas
authors.initials: L
authors.lastname: Sommer
authors.forename: Kurt
authors.initials: K
authors.lastname: Bürki
authors.forename: Paolo
authors.initials: P
authors.lastname: Cinelli
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D010064:Embryo Implantation / Q000235:genetics / Q000502:physiology; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000951:Antigens, Neoplasm; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009363:Neoplasm Proteins; C559377:Pramel6 protein, mouse; C559376:Pramel7 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse