title: The calcineurin-NFAT pathway negatively regulates megakaryopoiesis.
abstract: The calcium regulated calcineurin-nuclear factor of activated T cells (NFAT) pathway modulates the physiology of numerous cell types, including hematopoietic. Upon activation, calcineurin dephosphorylates NFAT family transcription factors, triggering their nuclear entry and activation or repression of target genes. NFATc1 and c2 isoforms are expressed in megakaryocytes. Moreover, human chromosome 21 (Hsa21) encodes several negative regulators of calcineurin-NFAT, candidates in the pathogenesis of Down syndrome (trisomy 21)-associated transient myeloproliferative disorder and acute megakaryoblastic leukemia. To investigate the role of calcineurin-NFAT in megakaryopoiesis, we examined wild-type mice treated with the calcineurin inhibitor cyclosporin A and transgenic mice expressing a targeted single extra copy of Dscr1, an Hsa21-encoded calcineurin inhibitor. Both murine models exhibited thrombocytosis with increased megakaryocytes and megakaryocyte progenitors. Pharmacological or genetic inhibition of calcineurin in mice caused accumulation of megakaryocytes exhibiting enhanced 5-bromo-2'-deoxyuridine uptake and increased expression of messenger RNAs encoding CDK4 and G1 cyclins, which promote cell division. Additionally, human megakaryocytes with trisomy 21 show increased proliferation and decreased NFAT activation compared with euploid controls. Our data indicate that inhibition of calcineurin-NFAT drives proliferation of megakaryocyte precursors by de-repressing genes that drive cell division, providing insights into mechanisms of normal megakaryopoiesis and megakaryocytic abnormalities that accompany Down syndrome.
authors: Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Alexander
authors: A
authors: Zaslavsky
authors: Stella T
authors: ST
authors: Chou
authors: Keri
authors: K
authors: Schadler
authors: Allyson
authors: A
authors: Lieberman
authors: Maxim
authors: M
authors: Pimkin
authors: Yeo Jung
authors: YJ
authors: Kim
authors: Kwan-Hyuck
authors: KH
authors: Baek
authors: William C
authors: WC
authors: Aird
authors: Mitchell J
authors: MJ
authors: Weiss
authors: Sandra
authors: S
authors: Ryeom
mesh_terms: D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010976:Platelet Count; D015398:Signal Transduction; D034061:Thrombopoiesis
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D019703:Calcineurin