Molecular and transcriptional regulation of megakaryocyte differentiation

Megakaryocytes, among the rarest of hematopoietic cells, serve the essentia l function of producing numerous platelets. Genetic studies have recently p rovided rich insights into the molecular and transcriptional regulation of megakaryocyte differentiation and thrombopoiesis. Three transcription facto rs, GATA-1, FOG-1, and NF-E2, are essential regulators of distinct stages i n megakaryocyte differentiation, extending from the birth of early committe d progenitors to the final step of platelet release; a fourth factor, Fli-1 , likely also plays an important role. The putative transcriptional targets of these regulators, including the NF-E2-dependent hematopoietic-specific beta -tubulin isoform beta1, deepen our understanding of molecular mechanis ms in platelet biogenesis. The study of rare syndromes of inherited thrombo cytopenia in mice and man has also refined the emerging picture of megakary ocyte maturation. Synthesis of platelet-specific organelles is mediated by a variety of regulators of intracellular vesicle membrane fusion, and plate let release is coordinated through extensive and dynamic reorganization of the actin and microtubule cytoskeletons. As in other aspects of hematopoies is, characterization of recurrent chromosomal translocations in human leuke mias provides an added dimension to the molecular underpinnings of megakary ocyte differentiation. Long regarded as a mysterious cell, the megakaryocyt e is thus yielding many of its secrets, and mechanisms of thrombopoiesis ar e becoming clearer. Although this review focuses on transcriptional control mechanisms, it also discusses recent advances in broader consideration of the birth of platelets.