This Article Full Text Full Text (PDF) All Versions of this Article: 29/11/1874    most recent ATVBAHA.109.193805v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Bernard, J. J. Articles by Phipps, R. P. PubMed PubMed Citation Articles by Bernard, J. J. Articles by Phipps, R. P.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1874.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Foxp3 Regulates Megakaryopoiesis and Platelet Function

Jamie J. Bernard; Kathryn E. Seweryniak; Anne D. Koniski; Sherry L. Spinelli; Neil Blumberg; Charles W. Francis; Mark B. Taubman; James Palis; Richard P. Phipps

From the Department of Environmental Medicine and the Lung Biology and Disease Program (J.J.B., K.E.S., R.P.P.), the Center for Pediatric Biomedical Research (A.D.K.), and the Departments of Pathology and Laboratory Medicine (S.L.S., N.B., R.P.P.), Medicine (C.W.F., M.B.T., R.P.P.), and Pediatrics (J.P., R.P.P.), University of Rochester, NY.

Correspondence to Richard P. Phipps, Department of Environmental Medicine, Box 850, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642. E-mail richard_phipps{at}URMC.rochester.edu

Objective— Platelets are crucial for hemostasis and are vital regulators of inflammation. Foxp3 is a key transcription factor for T regulatory cell development. Humans with IPEX (immune dysregulation, polyendocrinopathy, enteropathy, x-linked) and the scurfy (Foxp3^sf) mouse have mutations in the Foxp3 gene that lead to a host of pathologies including autoimmunity and skin diseases. Scurfy mice and some humans with IPEX are also thrombocytopenic. The purpose of this study was to determine whether the absence of functional Foxp3 leads to defects in megakaryocytes and platelets.

Methods and Results— We discovered that human and mouse megakaryocytes express Foxp3 mRNA and protein. Using shRNA and Foxp3^sf mice, we demonstrated that Foxp3-deficient mouse and human megakaryocyte progenitors exhibited proliferation defects. Striking platelet abnormalities were observed in both an IPEX patient and Foxp3^sf mice. Impaired platelet spreading and release of TGF-β and CD40 ligand (CD40L), and abnormal levels of plasma CD40L were observed in a case of IPEX syndrome. Foxp3^sf mice were thrombocytopenic and had increased platelet volume and altered serum levels of CD40L, TXB₂, and TGF-β.

Conclusion— These findings provide compelling new evidence that Foxp3 is needed for proper megakaryopoiesis and plays a role in regulating platelet function including spreading and release.

We discovered that human and mouse megakaryocytes express Foxp3 mRNA and protein. Humans with IPEX and the scurfy (Foxp3^sf) mouse have mutations in the Foxp3 gene that lead to autoimmunity, skin diseases, hemorrhage, and thrombocytopenia. Our studies suggest that Foxp3 is needed for proper megakaryopoiesis and platelet function.

Key Words: megakaryocytes • platelets • Foxp3 • IPEX