The Microtubule Plus-End Tracking Protein CLASP2 Is Required for Hematopoiesis and Hematopoietic Stem Cell Maintenance
Ksenija Drabek,
Laura Gutiérrez,
Marcel Vermeij,
Thomas Clapes,
Sunita R. Patel,
Jean-Charles Boisset,
Jeffrey van Haren,
Ana L. Pereira,
Zhe Liu,
Umut Akinci,
Tatjana Nikolic,
Wilfred van IJcken,
Mirjam van den Hout,
Marjolein Meinders,
Clara Melo,
Clara Sambade,
Dubravka Drabek,
Rudi W. Hendriks,
Sjaak Philipsen,
Mieke Mommaas,
Frank Grosveld,
Helder Maiato,
Joseph E. Italiano, Jr.,
Catherine Robin,
Niels Galjart
Affiliations
Ksenija Drabek
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Laura Gutiérrez
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Marcel Vermeij
Department of Pathology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Thomas Clapes
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Sunita R. Patel
Hematology Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Jean-Charles Boisset
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Jeffrey van Haren
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Ana L. Pereira
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Zhe Liu
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Umut Akinci
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Tatjana Nikolic
Department of Pulmonary Medicine, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Wilfred van IJcken
Erasmus Center for Biomics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Mirjam van den Hout
Erasmus Center for Biomics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Marjolein Meinders
Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands
Clara Melo
Chromosome Instability & Dynamics Laboratory-Instituto de Biologia Molecular e Celular, Faculdade de Medicina, Universidade do Porto, 4200-465 Porto, Portugal
Clara Sambade
Cancer Biology, IPATIMUP, and Medical Faculty of Porto, Faculdade de Medicina, Universidade do Porto, 4200-465 Porto, Portugal
Dubravka Drabek
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Rudi W. Hendriks
Department of Pulmonary Medicine, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Sjaak Philipsen
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Mieke Mommaas
Center for Electron Microscopy, Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RA Leiden, The Netherlands
Frank Grosveld
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Helder Maiato
Chromosome Instability & Dynamics Laboratory-Instituto de Biologia Molecular e Celular, Faculdade de Medicina, Universidade do Porto, 4200-465 Porto, Portugal
Joseph E. Italiano, Jr.
Hematology Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Catherine Robin
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Niels Galjart
Department of Cell Biology and Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.
