All in the family: Primary megakaryocytes for studies of platelet alpha IIb beta(3) signaling

Integrin alpha IIb beta3 mediates key platelet adhesive responses during he mostasis and thrombosis. Adhesive ligand binding to alpha IIb beta3 is regu lated by "inside-out" signals, while adhesion-dependent cytoskeletal events are regulated by "outside-in" signals from alpha IIb beta3. Currently, the molecular basis of bidirectional alpha IIb beta3 signaling is incompletely understood. The functional assessment of integrin signaling pathways in nu cleated cells has been facilitated by techniques such as viral transduction which enable expression of dominant-active and dominant-inhibitory gene pr oducts. This approach cannot be used with anucleate platelets. However, rec ent advances in the ability to expand human and murine megakaryocytes from hematopoietic stem cells provide a tractable and genetically manipulatable system for studies of alpha IIb beta3 signaling. This overview will discuss some of the advantages and limitations of this approach and provide exampl es of its utility. Thus, in addition to their intrinsic value for understan ding hematopoiesis and platelet formation, primary megakaryocytes represent a model system complementary to platelets for unraveling the remaining mys teries of alpha IIb beta3 signaling.