title: Inefficient megakaryopoiesis in mouse hematopoietic stem-progenitor cells lacking T-bet.
abstract: Differentiation of hematopoietic stem-progenitor cells (HSPCs) into mature blood lineages results from the translation of extracellular signals into changes in the expression levels of transcription factors controlling cell fate decisions. Multiple transcription factor families are known to be involved in hematopoiesis. Although the T-box transcription factor family is known to be involved in the differentiation of multiple tissues, and expression of T-bet, a T-box family transcription factor, has been observed in HSPCs, T-box family transcription factors do not have a described role in HSPC differentiation. In the current study, we address the functional consequences of T-bet expression in mouse HSPCs. T-bet protein levels differed among HSPC subsets, with highest levels observed in megakaryo-erythroid progenitor cells (MEPs), the common precursor to megakaryocytes and erythrocytes. HSPCs from T-bet-deficient mice exhibited a defect in megakaryocytic differentiation when cultured in the presence of thrombopoietin. In contrast, erythroid differentiation in culture in the presence of erythropoietin was not substantially altered in T-bet-deficient HSPCs. Differences observed with respect to megakaryocyte number and maturity, as assessed by level of expression of CD41 and CD61, and megakaryocyte ploidy, in T-bet-deficient HSPCs were not associated with altered proliferation or survival in culture. Gene expression micro-array analysis of MEPs from T-bet-deficient mice exhibited diminished expression of multiple genes associated with the megakaryocyte lineage. These data advance our understanding of the transcriptional regulation of megakaryopoiesis by supporting a new role for T-bet in the differentiation of MEPs into megakaryocytes.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Center for Stem Cell Research and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Aki
authors.initials: A
authors.lastname: Furusawa
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Center for Stem Cell Research and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sadashivaiah
authors.affiliation: Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Zeba N
authors.initials: ZN
authors.lastname: Singh
authors.affiliation: Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Center for Stem Cell Research and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD; Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Curt I
authors.initials: CI
authors.lastname: Civin
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD; Center for Stem Cell Research and Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD. Electronic address: abanerjee@som.umaryland.edu.
authors.forename: Arnob
authors.initials: A
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D039661:Integrin beta3 / Q000096:biosynthesis / Q000235:genetics; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000172:deficiency*; D000098815:T-bet Transcription Factor
chemical_list: D039661:Integrin beta3; D040201:Platelet Membrane Glycoprotein IIb; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor