title: Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment.
abstract: During hematopoiesis, transcriptional programs are essential for the commitment and differentiation of progenitors into the different blood lineages. GATA1 is a transcription factor expressed in several hematopoietic lineages and essential for proper erythropoiesis and megakaryopoiesis. Megakaryocyte-specific genes, such as GP1BA, are known to be directly regulated by GATA1. Mutations in GATA1 can lead to dyserythropoietic anemia and pseudo gray-platelet syndrome. Selective loss of Gata1 expression in adult mice results in macrothrombocytopenia with platelet dysfunction, characterized by an excess of immature megakaryocytes. To specifically analyze the impact of Gata1 loss in mature committed megakaryocytes, we generated Gata1-Lox|Pf4-Cre mice (Gata1cKOMK). Consistent with previous findings, Gata1cKOMK mice are macrothrombocytopenic with platelet dysfunction. Supporting this notion we demonstrate that Gata1 regulates directly the transcription of Syk, a tyrosine kinase that functions downstream of Clec2 and GPVI receptors in megakaryocytes and platelets. Furthermore, we show that Gata1cKOMK mice display an additional aberrant megakaryocyte differentiation stage. Interestingly, these mice present a misbalance of the multipotent progenitor compartment and the erythroid lineage, which translates into compensatory stress erythropoiesis and splenomegaly. Despite the severe thrombocytopenia, Gata1cKOMK mice display a mild reduction of TPO plasma levels, and Gata1cKOMK megakaryocytes show a mild increase in Pf4 mRNA levels; such a misbalance might be behind the general hematopoietic defects observed, affecting locally normal TPO and Pf4 levels at hematopoietic stem cell niches.
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Meinders
authors.affiliation: Dept. of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, AMC, UvA, Amsterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Hoogenboezem
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
authors.forename: Maaike R
authors.initials: MR
authors.lastname: Scheenstra
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: De Cuyper
authors.affiliation: Dept. of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
authors.forename: Petros
authors.initials: P
authors.lastname: Papadopoulos
authors.affiliation: Dept. of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.|MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Németh
authors.affiliation: Dept. of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.|MTA-SE "Lendület" Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.|Emma Children's Hospital, Academic Medical Centre (AMC), UvA, Amsterdam, the Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.affiliation: Dept. of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.|Dept. of Hematology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain.
authors.forename: Laura
authors.identifier: 0000-0001-8443-900X
authors.initials: L
authors.lastname: Gutiérrez
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D004797:Enzyme-Linked Immunosorbent Assay; D050982:GATA1 Transcription Factor / Q000235:genetics*; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014158:Transcription, Genetic
chemical_list: D050982:GATA1 Transcription Factor