Hervé Falet, PhD

Hervé Hervé profile

Hervé Falet, PhD

Investigator

Hemostasis, Thrombosis and Vascular Biology

Assistant Professor
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

Contact Information
  • 414-937-3870
  • 414-937-3870
  • 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

    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).

     
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