Canonical Wnt signaling in megakaryocytes regulates proplatelet formation

被引：38

作者：

Macaulay, Iain C. ^{[1
]}

Thon, Jonathan N. ^{[2
]}

Tijssen, Marloes R. ^{[4
,5
]}

Steele, Brian M. ^{[1
]}

MacDonald, Bryan T. ^{[3
]}

Meade, Gerardene ^{[6
]}

Burns, Philippa ^{[4
,5
]}

Rendon, Augusto ^{[4
,5
,7
]}

Salunkhe, Vishal ^{[1
]}

Murphy, Ronan P. ^{[6
]}

Bennett, Cavan ^{[4
,5
]}

Watkins, Nicholas A. ^{[4
,5
]}

He, Xi ^{[3
]}

Fitzgerald, Desmond J. ^{[1
]}

Italiano, Joseph E., Jr. ^{[2
,8
]}

Maguire, Patricia B. ^{[1
]}

机构：

[1] Univ Coll Dublin, UCD Conway Inst, Sch Biomed & Biomol Sci, Dublin 4, Ireland

[2] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Neurol, FM Kirby Neurobiol Ctr,Childrens Hosp Boston, Boston, MA 02115 USA

[4] Univ Cambridge, Dept Haematol, Cambridge, England

[5] Natl Hlth Serv Blood & Transplant, Cambridge, England

[6] Dublin City Univ, Fac Sci & Hlth, Sch Hlth & Human Performance, Dublin 9, Ireland

[7] MRC Biostat Unit, Cambridge, England

[8] Childrens Hosp, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA

来源：

BLOOD | 2013年 / 121卷 / 01期

基金：

爱尔兰科学基金会; 美国国家卫生研究院;

关键词：

WNT/BETA-CATENIN PATHWAY; HEMATOPOIETIC STEM-CELL; BETA-CATENIN; MOLECULAR-MECHANISMS; ENDOTHELIAL-CELLS; GENE-EXPRESSION; PROTEIN; MICE; THROMBOPOIESIS; MEGAKARYOPOIESIS;

D O I：

10.1182/blood-2012-03-416875

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 beta-catenin expression. beta-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. (Blood. 2013; 121(1): 188-196)

引用

页码：188 / 196

页数：9

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[21] Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins [J].

Macaulay, Iain C. ;

Tijssen, Marloes R. ;

Thijssen-Timmer, Daphne C. ;

Gusnanto, Arief ;

Steward, Michael ;

Burns, Philippa ;

Langford, Cordelia F. ;

Ellis, Peter D. ;

Dudbridge, Frank ;

Zwaginga, Jaap-Jan ;

Watkins, Nicholas A. ;

van der Schoot, C. Ellen ;

Ouwehand, Willem H. .

BLOOD, 2007, 109 (08) :3260-3269

[22] Contrasting responses of lymphoid progenitors to canonical and noncanonical Wnt signals [J].

Malhotra, Sachin ;

Baba, Yoshihiro ;

Garrett, Karla P. ;

Staal, Frank J. T. ;

Gerstein, Rachel ;

Kincade, Paul W. .

JOURNAL OF IMMUNOLOGY, 2008, 181 (06) :3955-3964

[23] Wnt-Related Molecules and Signaling Pathway Equilibrium in Hematopoiesis [J].

Malhotra, Sachin ;

Kincade, Paul W. .

CELL STEM CELL, 2009, 4 (01) :27-36

[24] Purified Wnt5a protein activates or inhibits β-catenin-TCF signaling depending on receptor context [J].

Mikels, AJ ;

Nusse, R .

PLOS BIOLOGY, 2006, 4 (04) :570-582

[25] Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways [J].

Nemeth, Michael J. ;

Bodine, David M. .

CELL RESEARCH, 2007, 17 (09) :746-758

[26] Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation [J].

Nemeth, Michael J. ;

Topol, Lilia ;

Anderson, Stacie M. ;

Yang, Yingzi ;

Bodine, David M. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (39) :15436-15441

[27] Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins [J].

O'Connor, Marie N. ;

Salles, Isabelle I. ;

Cvejic, Ana ;

Watkins, Nicholas A. ;

Walker, Adam ;

Garner, Stephen F. ;

Jones, Chris I. ;

Macaulay, Iain C. ;

Steward, Michael ;

Zwaginga, Jaap-Jan ;

Bray, Sarah L. ;

Dudbridge, Frank ;

de Bono, Bernard ;

Goodall, Alison H. ;

Deckmyn, Hans ;

Stemple, Derek L. ;

Ouwehand, Willem H. .

BLOOD, 2009, 113 (19) :4754-4762

[28] GSK-3β negatively regulates megakaryocyte differentiation and platelet production from primary human bone marrow cells in vitro [J].

Ono, Mayumi ;

Matsubara, Yumiko ;

Shibano, Toshiro ;

Ikeda, Yasuo ;

Murata, Mitsuru .

PLATELETS, 2011, 22 (03) :196-203

[29] Differential roles of microtubule assembly and sliding in proplatelet formation by megakaryocytes [J].

Patel, SR ;

Richardson, JL ;

Schulze, H ;

Kahle, E ;

Galiart, N ;

Drabek, K ;

Shivdasani, RA ;

Hartwig, JH ;

Italiano, JE .

BLOOD, 2005, 106 (13) :4076-4085

[30] The biogenesis of platelets from megakaryocyte propatelets [J].

Patel, SR ;

Hartwig, JH ;

Italiano, JE .

JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (12) :3348-3354

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