Canonical Wnt Signaling Regulates Hematopoiesis in a Dosage-Dependent Fashion

SummaryCanonical 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.

Graphical AbstractFigure optionsDownload high-quality image (147 K)Download as PowerPoint slideHighlights
► Canonical Wnt signaling is differentially regulated during hematopoiesis
► Mild levels of Wnt activation increase HSC whereas high Wnt dosage is detrimental
► Intermediate levels of Wnt signaling increase clonogenicity and myeloid development
► Early T cell development is enhanced by intermediate-high levels of Wnt signaling