Hervé Falet, PhD
Hervé Falet, PhD
Department of Cell Biology, Neurobiology and Anatomy
The Medical College of Wisconsin
Education and Training
Postdoctoral: Medicine, Brigham and Women's Hospital/Harvard Medical School, 2001
PhD: Molecular and Cellular Biology, Paris Descartes University, 1997
MS: Molecular Pharmacology, Paris Descartes University, 1993
My primary research interests are associated with deciphering the cellular mechanisms and proteins regulating normal and abnormal blood platelet production and function. Deficient thrombopoiesis (platelet production), due to genetic causes, secondary to cancer therapy, or from unknown etiology, poses significant risks of mortality, mostly due to bleeding. Blood platelets are produced in the bone marrow by megakaryocytes (MKs), a process that requires extensive intracellular membrane rearrangements, including the formation of the demarcation membrane system (DMS), the surface-connected membrane extension that provides membranes for future platelets. My current research is focused on the role of two endocytic proteins, the large GTPase dynamin 2 (DNM2) and the Fes/CIP4 homology Bin/Amphiphysin/Rvs (F-BAR) protein PACSIN2, in the formation and organization of the MK DMS.
Through its role in vesicle membrane fission, DNM2 is involved in a wide range of cellular functions, including endocytosis and vesicle transport. In humans, DNM2 mutations have been associated with Charcot-Marie-Tooth disease, centronuclear myopathy and T-cell acute lymphoblastic leukemia. We have generated Dnm2fl/fl Pf4-Cre (Dnm2Plt–/–) mice specifically lacking DNM2 in the MK lineage and have shown that Dnm2Plt–/– mice develop severe thrombocytopenia with large platelets and altered DMS formation due to accumulation of clathrin-coated vesicles in MKs (Bender, Giannini et al. Blood 2015;125(6):1014-1024). Dnm2Plt–/– mice also develop massive MK hyperplasia, myelofibrosis, extramedullary hematopoiesis and severe splenomegaly, demonstrating that DNM2-dependent endocytosis is required for normal MK development and bone marrow homeostasis.
PACSIN2 belongs to the F-BAR family of proteins that bind lipid bilayers to generate membrane tubular invaginations reminiscent of the MK DMS. We have identified PACSIN2 as an internal component of the initiating DMS (Begonja, Pluthero et al. Blood 2015;126(1):80-88), and have begun to determine the role of PACSIN2 in MKs and platelets by studying Pacsin2–/– mice. Pacsin2–/– mice develop mild thrombocytopenia with shallow platelets, MK hyperplasia and splenomegaly. By generating Pacsin2–/– Dnm2Plt–/– mice, we found that PACSIN2 deletion significantly improves the severe thrombocytopenia and MK DMS defects of Dnm2Plt–/– mice. These striking results are the basis of my NIH/NHLBI R01 grant award.
In summary, our research addresses the gap of knowledge on endocytosis in blood platelet production and function. We anticipate that findings obtained from these studies will yield better understanding to obtain basic science information on how membrane rearrangements contribute to platelet production and function, and to develop treatments for effective re-establishment of platelet production in the setting of thrombocytopenia.
NIH/NHLBI R01 HL126743 Endocytosis in platelet and megakaryocyte biology, 08/01/16–05/31/20
- Crescente M, Pluthero FG, Li L, Lo RW, Walsh TG, Schenk MP, Holbrook LM, Louriero S, Ali MS, Vaiyapuri S, Falet H, Jones IM, Poole AW, Kahr WH, Gibbins JM. Intracellular trafficking, localization, and mobilization of platelet-borne thiol isomerases. Arterioscler Thromb Vasc Biol 2016;36(6):1164-1173
- Grozovsky R, Giannini S, Falet H, Hoffmeister KM. Regulating billions of blood platelets: glycans and beyond. Blood 2015;126 (16):1877-1884
- Begonja AJ, Pluthero FG, Suphamungmee W, Giannini S, Christensen H, Leung R, Lo R, Nakamura F, Lehman W, Plomann M, Hoffmeister KM, Kahr WHA, Hartwig JH, Falet H. FlnA binding to PACSIN2 F- BAR domain regulates membrane tubulation in megakaryocytes and platelets. Blood 2015;126(1):80-88
- Bender M, Giannini S, Grozovsky R, Jönsson T, Christensen H, Pluthero FG, Ko A, Mullally A, Kahr WHA, Hoffmeister KM, Falet H. Dynamin 2-dependent endocytosis is required for normal megakaryocyte development in mice. Blood 2015;125(6):1014-1024
- Grozovsky R, Begonja AJ, Liu K, Visner G, Hartwig JH, Falet H, Hoffmeister KM. The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 2015;21(1):47-54
- Bender M, Stritt S, Nurden P, van Eeuwijk JM, Zieger B, Kentouche K, Schulze H, Morbach H, Stegner D, Heinze K, Dütting S, Gupta S, Witke W, Falet H, Fischer A, Hartwig JH, Nieswandt B. Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott-Aldrich syndrome-like platelet defect. Nat Commun 2014;5:4746
- Kim H, Falet H, Hoffmeister KM, Hartwig JH. Wiskott-Aldrich syndrome protein (WASp) controls the delivery of platelet transforming growth factor-β1. J Biol Chem 2013;288(48):34352-34363
- Recher M, Burns SO, de la Fuente MA, Volpi S, Dahlberg C, Walter JE, Moffitt K, Mathew D, Honke N, Lang PA, Patrizi L, Falet H, Keszei M, Mizui M, Csizmadia E, Candotti F, Nadeau K, Bouma G, Delmonte OM, Frugoni F, Fomin AB, Buchbinder D, Lundequist EM, Massaad MJ, Tsokos GC, Hartwig J, Manis J, Terhorst C, Geha RS, Snapper S, Lang KS, Malley R, Westerberg L, Thrasher AJ, Notarangelo LD. B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood 2012;119(12):2819-2828
- Jansen AJ, Josefsson EC, Rumjantseva V, Liu QP, Falet H, Bergmeier W, Cifuni SM, Sackstein R, von Andrian UH, Wagner DD, Hartwig JH, Hoffmeister KM. Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice. Blood 2012;119(5):1263-1273
- Begonja AJ, Hoffmeister KM, Hartwig JH, Falet H. FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly. Blood 2011;118(8):2285-2295
- Falet H, Pollitt AY, Begonja AJ, Weber SE, Duerschmied D, Wagner DD, Watson SP, Hartwig JH. A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function. J Exp Med 2010;107(9):1967-1979
Research positions at various levels are available in the Falet lab to study the role of endocytosis in platelet and megakaryocyte biology. To apply, please submit a CV, statement of qualifications, and references to Dr Hervé Falet (HFalet@Versiti.org).