title: The GM-CSF receptor utilizes β-catenin and Tcf4 to specify macrophage lineage differentiation.
abstract: Granulocyte-macrophage colony stimulating factor (GM-CSF) promotes the growth, survival, differentiation and activation of normal myeloid cells and is essential for fully functional macrophage differentiation in vivo. To better understand the mechanisms by which growth factors control the balance between proliferation and self-renewal versus growth-suppression and differentiation we have used the bi-potent FDB1 myeloid cell line, which proliferates in IL-3 and differentiates to granulocytes and macrophages in response to GM-CSF. This provides a manipulable model in which to dissect the switch between growth and differentiation. We show that, in the context of signaling from an activating mutant of the GM-CSF receptor β subunit, a single intracellular tyrosine residue (Y577) mediates the granulocyte fate decision. Loss of granulocyte differentiation in a Y577F second-site mutant is accompanied by enhanced macrophage differentiation and accumulation of β-catenin together with activation of Tcf4 and other Wnt target genes. These include the known macrophage lineage inducer, Egr1. We show that forced expression of Tcf4 or a stabilised β-catenin mutant is sufficient to promote macrophage differentiation in response to GM-CSF and that GM-CSF can regulate β-catenin stability, most likely via GSK3β. Consistent with this pathway being active in primary cells we show that inhibition of GSK3β activity promotes the formation of macrophage colonies at the expense of granulocyte colonies in response to GM-CSF. This study therefore identifies a novel pathway through which growth factor receptor signaling can interact with transcriptional regulators to influence lineage choice during myeloid differentiation.
authors.affiliation: Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Brown
authors.forename: Diana G
authors.initials: DG
authors.lastname: Salerno
authors.forename: Teresa
authors.initials: T
authors.lastname: Sadras
authors.forename: Grant A
authors.initials: GA
authors.lastname: Engler
authors.forename: Chung H
authors.initials: CH
authors.lastname: Kok
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Wilkinson
authors.forename: Saumya E
authors.initials: SE
authors.lastname: Samaraweera
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sadlon
authors.forename: Michelle
authors.initials: M
authors.lastname: Perugini
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006098:Granulocytes / Q000166:cytology; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction; D000073940:Transcription Factor 4; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495267:CTNNB1 protein, mouse; D053648:Cytokine Receptor Common beta Subunit; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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