Canonical Wnt Signaling in Megakaryocytes Regulates Proplatelet Formation

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2012 Nov 20

PMID 23160460

Citations 24

Authors

Iain C Macaulay

Jonathan N Thon

Marloes R Tijssen

Brian M Steele

Bryan T MacDonald

Gerardene Meade

Philippa Burns

Augusto Rendon

Vishal Salunkhe

Ronan P Murphy

Cavan Bennett

Nicholas A Watkins

Xi He

Desmond J Fitzgerald

Joseph E Italiano Jr

Patricia B Maguire

Affiliations

Soon will be listed here.

Abstract

Wnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and noncanonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 cell line as a model for human MKs, the canonical Wnt3a signal was found to induce a time and dose-dependent increase in β-catenin expression. β-catenin accumulation was inhibited by the canonical antagonist dickkopf-1 (DKK1) and by the noncanonical agonist Wnt5a. Whole genome expression analysis demonstrated that Wnt3a and Wnt5a regulated distinct patterns of gene expression in MKs, and revealed a further interplay between canonical and noncanonical Wnt pathways. Fetal liver cells derived from low-density-lipoprotein receptor-related protein 6-deficient mice (LRP6(-/-)), generated dramatically reduced numbers of MKs in culture of lower ploidy (2N and 4N) than wild-type controls, implicating LRP6-dependent Wnt signaling in MK proliferation and maturation. Finally, in wild-type mature murine fetal liver-derived MKs, Wnt3a potently induced proplatelet formation, an effect that could be completely abrogated by DKK1. These data identify novel extrinsic regulators of proplatelet formation, and reveal a profound role for Wnt signaling in platelet production.

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