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γ-Catenin is expressed throughout normal human hematopoietic development and is required for normal PU.1-dependent monocyte differentiation

Leukemia volume 27, pages 2096–2100 (2013)Cite this article

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Wnt signaling is an evolutionary, conserved pathway critical for normal development. In the absence of a Wnt stimulus, the pathway is suppressed through constitutive degradation of the central mediator β-catenin. While in this state, TCF/LEF family members remain DNA-bound in a transcriptionally repressive complex with Groucho, CtBP and histone deacetylases.1 In the presence of a Wnt ligand, degradation of β-catenin is inhibited, leading to stabilization and nuclear translocation of this protein. In the nucleus, β-catenin serves as a transcriptional co-activator by displacing repressive elements on TCF/LEF factors such as TCF7L2 (aka TCF4), and stimulating Wnt target gene transcription.2 There is conflicting evidence in the literature concerning the role of canonical Wnt signaling in hematopoiesis. Some studies suggest the pathway is important for normal hematopoietic stem cell (HSC) self-renewal and development, whereas others demonstrate how constitutive activation impairs differentiation and exhausts the HSC pool (reviewed by Staal and Luis1). In the context of hematological malignancy, the aberrant expression/activity of β-catenin has frequently been reported in leukemia, and may contribute to the establishment and maintenance of leukemia-initiating cells (reviewed by Fung et al.3). More recently, we have shown that dysregulation of a closely related Wnt signaling component, γ-catenin (aka plakoglobin), is also frequently overexpressed in acute myeloid leukemia4 and implicated in leukemogenesis.5 The role of γ-catenin and Wnt signaling in hematopoietic reconstitution is controversial,1 however, there have been no studies investigating whether γ-catenin influences hematopoietic differentiation. We, therefore, sought to characterize γ-catenin’s expression level, subcellular localization and importance to normal human hematopoiesis.

Within the epithelial context, γ-catenin has been characterized as a dual-function molecule with roles in both adhesion and transcription.8 As these roles are associated with distinct subcellular locations, we examined the intracellular localization of γ-catenin using a validated confocal laser scanning microscopy analysis (Supplementary Figure S4) in subpopulations exhibiting the highest expression levels (HSPC, granulocytes, monocytes). Purified CB-derived CD34+ cells demonstrated a predominantly cytoplasmic localization of γ-catenin protein; little protein could be detected within the nucleus of these cells and there was also no clear-membrane-associated γ-catenin as seen in epithelial cells9 (Figures 1c and f, and further color images are available in Supplementary Figure S5). This cytosolic pool of γ-catenin may serve a structural role or represent a reserve of protein available for nuclear translocation; however, in a previous study, we were unable to force the nuclear translocation of γ-catenin in these cells using Wnt agonists or ectopic expression.4 These data showed that expression level of cytoplasmic γ-catenin alone does not strongly influence its nuclear localization, indicating the need for additional cues to promote γ-catenin translocation in normal haematopoietic cells.

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Acknowledgements

Funding was provided by Leukemia and Lymphoma Research, Medical Research Council, UK and Cardiff University, UK. Rhys Morgan is funded by Kay Kendall Leukemia Research Fund.

Author contributions

RM co-wrote the manuscript, designed and executed experiments, and analyzed data. LP, KL and SLD provided technical assistance. AKB provided resources and clinical insight. RLD and AT designed experiments, analyzed data, provided project direction and co-wrote the manuscript.

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  1. R L Darley and A Tonks: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Wales, UK

    R G Morgan, K Liddiard, L Pearn, S L Pumford, A K Burnett, R L Darley & A Tonks

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  1. R G Morgan
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Correspondence to A Tonks.

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Morgan, R., Liddiard, K., Pearn, L. et al. γ-Catenin is expressed throughout normal human hematopoietic development and is required for normal PU.1-dependent monocyte differentiation. Leukemia 27, 2096–2100 (2013). https://doi.org/10.1038/leu.2013.96

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