title: IGF antagonizes the Wnt/β-Catenin pathway and promotes differentiation of extra-embryonic endoderm.
abstract: Mouse F9 teratocarcinoma cells are an established model for the differentiation of extra-embryonic endoderm (ExEn). Primitive endoderm, parietal and visceral endoderm can be generated by stimulation of F9 cells with retinoic acid and dibutyryl cyclic adenosine monophosphate. Here we show that Wnt/β-Catenin signaling is down-regulated during ExEn differentiation in F9 cells and that the inhibition of the Wnt pathway promotes differentiation of the three extra-embryonic endoderm lineages. Wnt inhibition is achieved through the IGF pathway, which is up-regulated during differentiation. IGF signaling antagonizes the Wnt pathway by stimulating transcription of axin2 and by stabilizing Axin1 protein. Both Axin1 and Axin2 are components of the β-Catenin destruction complex and act as intra-cellular inhibitors of the Wnt/β-Catenin pathway. The data presented reveal a mechanism which restricts pluripotency of undifferentiated cells and directs them toward extra-embryonic lineages.
authors.affiliation: Institute of Human Genetics, University Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address: judith.schlupf@gmx.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Schlupf
authors.affiliation: Institute of Human Genetics, University Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Steinbeisser
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D004707:Endoderm / Q000254:growth & development / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D060466:Axin Protein; C555452:Axin1 protein, mouse; C111729:Axin2 protein, mouse; D051176:beta Catenin; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I
keywords: Axin; Differentiation; Extra-embryonic endoderm; IGF pathway; Wnt pathway