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Megakaryocytopoiesis
and Platelet Function
Hematopoiesis is a life-long developmental process requiring maintenance
of a precursor/stem cell pool, generation of adequate numbers of circulating
mature blood cells, and the ability to individually modulate each developmental
lineage in response to specific needs of the organism. My lab uses murine
models to study megakaryocytopoiesis, the “branch” of hematopoiesis
that produces circulating platelets. We are currently studying the role
of the Raf family, especially Raf-1 and B-Raf, and Stat-5 signaling in
megakaryocytopoiesis.
Platelets play a critical role in clot formation through the binding of
fibrinogen by their surface integrin aIIbb3. The aIIbb3 on resting, circulating
platelets is unable to bind fibrinogen until the platelet is activated
by one or more platelet agonists, typically at the site of vascular injury.
The activation of aIIbb3 results in increased affinity and avidity of
aIIbb3 for its ligand and is called agonist-induced “inside-out”
signaling. We have demonstrated that inside-out signaling is developmentally
regulated during megakaryocytopoiesis and that megakaryocytes lacking
the transcription factor NF-E2 fail to undergo agonist induced aIIbb3
inside-out activation. We are currently using various methods of differential
expression analysis to identify the NF-E2 regulated genes that play a
role in the aIIbb3 inside-out signaling. These gene products should provide
useful targets for new classes of anti-platelet agents.
Selected Publications:
Murphy G and Leavitt AD. A model for studying megakaryocyte development
and biology. Proc. Natl. Acad. Sci., USA. 96:3065-70, 1999.
Shiraga M, Ritchie A, Aidoudi S, Baron V, Wilcox D, White G, Ybarrando
B, Murphy G, Leavitt AD, Shattil S. Primary megakaryocytes reveal
a role for transcription factor NF-E2 in integrin aIIbb3 signaling.
J. Cell Biol. 147:1419-29, 1999.
Chen, JC-H, Krucinsky J, Miercke LJW, Finer-Moore JS, Tang AH, Leavitt
AD, Stroud, RM. Crystal structure of the HIV-1 integrase catalytic
core and C-terminal domains: a model for viral DNA binding. Proc.
Natl. Acad. Sci., USA 97:8233-38, 2000.
Gaur M, Murphy GJ, deSauvage FJ, Leavitt AD. Characterization of Mpl mutants
using primary megakaryocyte-lineage cells from mpl-/- mice: a new system
for studying Mpl function. Blood 97:1653-61, 2001.
Shattil, S.J. and Leavitt, A.D. All in the family: primary
megakaryocytes for studies of platelet aIIbb3 Signaling. Thrombosis
and Haemostasis 86: 259-65, 2001.
Eto, K, Murphy, R. Bertoni A, Stuhlmann H. Nakano T. Leavitt AD, and Shattil,
SJ. Megakaryocytes from embryonic stem cells implicate CalDAG-GEFI
in integrin signaling. Proc. Natl. Acad. Sci., USA 99:12819-12824.
Contact Information:
Email: leavitta@labmed2.ucsf.edu
Phone: 415/514-3432
Address: Box 0100, Room S 555
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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