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Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphin‐gosine 1‐phosphate receptor 4 (S1P4) is specifically up‐regulated during the development of human megakaryo‐cytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P4‐deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4−/− mice. Remarkably, overexpression and stimulation of S1P4 in human eryth‐roleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet‐like particles. These observations indicate that S1P4 is involved in shaping the terminal differentiation of megakaryocytes.—Golfier, S., Kondo, S., Schulze, T., Takeuchi, T., Vassileva, G., Achtman, A. H., Graler, M. H., Abbondanzo, S. J., Wiekowski, M., Kremmer, E., Endo, Y., Lira, S. A., Bacon, K. B., Lipp, M. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine‐1‐phosphate receptor S1P4. FASEB J. 24, 4701–4710 (2010). www.fasebj.org [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphigosine 1-phosphate receptor 4 (S1P4) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P44-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopen was significantly delayed in S1p4-1- mice. Remarkabl overexpression and stimulation of S1P4 in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P is involved in shaping the terminal differentiation of megakaryocytes. [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphin‐gosine 1‐phosphate receptor 4 (S1P4) is specifically up‐regulated during the development of human megakaryo‐cytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P4‐deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4−/− mice. Remarkably, overexpression and stimulation of S1P4 in human eryth‐roleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet‐like particles. These observations indicate that S1P4 is involved in shaping the terminal differentiation of megakaryocytes.—Golfier, S., Kondo, S., Schulze, T., Takeuchi, T., Vassileva, G., Achtman, A. H., Graler, M. H., Abbondanzo, S. J., Wiekowski, M., Kremmer, E., Endo, Y., Lira, S. A., Bacon, K. B., Lipp, M. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine‐1‐phosphate receptor S1P4. FASEB J. 24, 4701–4710 (2010). www.fasebj.org [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphigosine 1-phosphate receptor 4 (S1P4) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P44-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopen was significantly delayed in S1p4-1- mice. Remarkabl overexpression and stimulation of S1P4 in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P is involved in shaping the terminal differentiation of megakaryocytes. [ABSTRACT FROM AUTHOR]