title: Canonical wnt signaling regulates hematopoiesis in a dosage-dependent fashion.
abstract: Canonical Wnt signaling has been implicated in the regulation of hematopoiesis. By employing a Wnt-reporter mouse, we observed that Wnt signaling is differentially activated during hematopoiesis, suggesting an important regulatory role for specific Wnt signaling levels. To investigate whether canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion, we analyzed the effect of different mutations in the Adenomatous polyposis coli gene (Apc), a negative modulator of the canonical Wnt pathway. By combining different targeted hypomorphic alleles and a conditional deletion allele of Apc, a gradient of five different Wnt signaling levels was obtained in vivo. We here show that different, lineage-specific Wnt dosages regulate hematopoietic stem cells (HSCs), myeloid precursors, and T lymphoid precursors during hematopoiesis. Differential, lineage-specific optimal Wnt dosages provide a unifying concept that explains the differences reported among inducible gain-of-function approaches, leading to either HSC expansion or depletion of the HSC pool.
authors: Department of Immunology, Erasmus University Medical Center, The Netherlands.
authors: Tiago C
authors: TC
authors: Luis
authors: Brigitta A E
authors: BA
authors: Naber
authors: Paul P C
authors: PP
authors: Roozen
authors: Martijn H
authors: MH
authors: Brugman
authors: Edwin F E
authors: EF
authors: de Haas
authors: Mehrnaz
authors: M
authors: Ghazvini
authors: Willem E
authors: WE
authors: Fibbe
authors: Jacques J M
authors: JJ
authors: van Dongen
authors: Riccardo
authors: R
authors: Fodde
authors: Frank J T
authors: FJ
authors: Staal
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002999:Clone Cells; D005434:Flow Cytometry; D018628:Gene Dosage; D018390:Gene Targeting; D006410:Hematopoiesis; D006413:Hematopoietic System / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D060449:Wnt Signaling Pathway