title: Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation.
abstract: Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt-regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells.
authors: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
authors: Yaser
authors: Y
authors: Atlasi
authors: Rubina
authors: R
authors: Noori
authors: Claudia
authors: C
authors: Gaspar
authors: Patrick
authors: P
authors: Franken
authors: Andrea
authors: A
authors: Sacchetti
authors: Haleh
authors: H
authors: Rafati
authors: Tokameh
authors: T
authors: Mahmoudi
authors: Charles
authors: C
authors: Decraene
authors: George A
authors: GA
authors: Calin
authors: Bradley J
authors: BJ
authors: Merrill
authors: Riccardo
authors: R
authors: Fodde
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D019175:DNA Methylation; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D009154:Mutation; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051792:Basic Helix-Loop-Helix Proteins; C075668:Tcf3 protein, mouse
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