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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-11-3553.
Submitted November 22, 2002
Accepted March 14, 2003
NMDA receptor-mediated regulation of human megakaryocytopoiesis
Ian S Hitchcock, Timothy M Skerry, Martin R Howard, and Paul G Genever*
Department of Biology, University of York, York, United Kingdom
Department of Clinical Haematology, York NHS Trust, York, United Kingdom
Department of Veterinary Basic Sciences, Royal Veterinary College, London, United Kingdom
* Corresponding author; email: pg5{at}york.ac.uk.
Identification of the regulatory inputs that direct megakaryocytopoiesis and platelet production is essential for the development of novel therapeutic strategies for the treatment of thrombosis and related hematological disorders. We have previously shown that primary human megakaryocytes express the NR1 subunit of NMDA-type glutamate receptors, which appears to be pharmacologically similar to those identified at neuronal synapses, responsible for mediating excitatory neurotransmission in the central nervous system. However, the functional role of NMDA receptor signaling in megakaryocytopoiesis remains unclear. Here we provide evidence that demonstrates the fundamental importance of this signaling pathway during human megakaryocyte maturation in vitro. RT-PCR analysis of RNA extracted from CD34+ derived megakaryocytes, identified expression of NR2A and NR2D receptor subunits in these cells, as well as the NMDA receptor accessory proteins, Yotiao and PSD-95. In functional studies, addition of the highly selective NMDA receptor antagonist, MK-801 inhibited proplatelet formation, without affecting proliferation or apoptosis. Exposure of MK-801 to CD34+ cells cultured for 14 days in the presence of thrombopoietin, induced a decrease in expression of the megakaryocyte cell surface markers CD61, CD41a and CD42a compared to controls. At an ultrastructural level, MK-801-treated cells lacked  -granules, demarcated membranes and multilobed nuclei, which were prominent in untreated mature megakaryocyte controls. Immunohistochemical studies using sections of whole tibiae from c-Mpl - knockout mice demonstrated that megakaryocytic NMDA receptor expression was maintained following c-Mpl ablation. These data support a fundamental role for glutamate signaling in megakaryocytopoiesis and platelet production, which is likely to be independent of thrombopoietin mediated effects.
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