[Frontiers in Bioscience 12, 2050-2062, January 1, 2007]

Megakaryopoiesis: Transcriptional Insights into Megakaryocyte Maturation

John C. Kostyak1, Ulhas P. Naik1,2,3,4

1Department of Biological Sciences, University of Delaware, Newark 2Department of Chemistry and Biochemistry, University of Delaware, Newark, 3Department of Chemical Engineering, University of Delaware, Newark 4Delaware Biotechnology Institute, University of Delaware, Newark

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Signaling Pathways Involved in Megakaryocyte Maturation
3.1. Thrombopoietin
3.2. TPO-Initiated Signaling in Megakaryocytes
3.3. Phosphatidylinositol 3-kinase
3.4. Mitogen Activated Protein Kinases
3.5. Stromal Cell-Derived Factor 1
3.6. Immediate Early Gene X-1
3.7. The Src Family Kinase; Lyn
4. Transcription Factors Associated with Megakaryopoiesis

4.1. GATA-1 and Its Cofactor FOG-1

4.2. Friend of GATA-1
4.3. Other GATA-1 Interactions
4.4. AML1/RUNX1 and Its Interactions Observed in Megakaryopoiesis
4.5. Nuclear Factor Erythroid-Derived 2
4.6. Other Factors Involved in Megakaryopoiesis
4.7.The Transcription Factor Fli-1
4.8. The Cap'n'colar BACH1
5. Summary
6. Acknowledgement
7. References

1. ABSTRACT

Platelets are small anucleate cells that travel near the vessel wall during laminar flow. In response to vascular injury, platelets undergo alterations in morphology which allow them to aggregate and cover the injured site. Platelets are produced by megakaryocytes in a process that involves the formation of platelet precursors called proplatelets and subsequent release of these proplatelets into the circulation. By forming a demarcation membrane system within the cytosol, megakaryocytes contain a membrane reservoir which allows for the production of thousands of platelets per mature megakaryocyte. Interestingly, the above process known as megakaryopoiesis is not yet fully understood. However, several groups have contributed evidence to unveil the role of thrombopoietin (TPO), the principal regulator of megakaryopoiesis in vivo. TPO is necessary for megakaryocyte maturation in that TPO deficient mice display greatly reduced megakaryocyte production as well as reduced numbers of mature megakaryocytes. Several transcription factors have also been implicated in megakaryopoiesis including, GATA-1, friend of GATA-1 (FOG-1), nuclear factor-erythroid 2 (NF-E2), and Fli-1. In fact, interactions among some of the transcription factors have been reported to produce synergistic effects. GATA-1 and Fli-1 interactions result in heightened GPIX and GPIb (2 components of von Willebrand Factor (vWF) receptor) expression, while GATA-1, RUNX1 and core-binding factor b interactions result in improved aIIb promoter activity. Mutations in the vWF complex and aIIbb3 have been linked to disorders such as Bernard-Soulier syndrome and Glazmann thrombasthenia respectively. Therefore, a more comprehensive understanding of the transcriptional control of megakaryopoiesis may lead to more effective treatments of platelet-related disorders.