Molecular and in vivo Functional Analysis of Disabled-2 in Megakaryopoiesis and Platelet Biogenesis

Platelets are anucleated cells derived from megakaryocytes and represent the second most numerous blood cells in the peripheral blood. Appropriate control of platelet production is important for the maintenance of normal human physiological haemostasis. During platelet biogenesis, proplatelet is first formed that appears as the thin tread structure protruding from the megakaryocyte. The breakdown of proplatelet consequently results in the production of platelets. Although the phenomenon has been known for years, the key regulators in the control of megakaryocytic differentiation and proplatelet formation are not yet completely understood. Among the platelet and megakaryocyte proteins, Disabled-2 (DAB2) has been implicates in endocytosis, cellular adhesive function, and hematopoietic cell differentiation and is closely associated with in vitro and ex vivo megakaryocytic differentiation. We therefore address in this grant proposal to determine whether DAB2 plays a key role during in vivo megakaryocytic maturation and platelet biogenesis. At the first 1 1/2 years, we will characterize the effects of DAB2 on megakaryocyte maturation and platelet biogenesis using the DAB2 megakaryocyte lineage-specific conditional knockout mice. At the second year, we will set up a biotinylation-affinity protein immobilized system and will use proteomic approach to identify DAB2-interacting proteins in megakaryocytes. At the third year, we will determine the functional significance of such interactions in megakaryocytic differentiation and platelet biogenesis. This study thereby will shed new insight for the molecular mechanisms in megakaryocyte and platelet biology and the functional role of DAB2 expression in the maturation of megakaryocyte and platelet.

Project ID:PC9907-2511
External Project ID:NSC99-2628-B182-001-MY3