Repercussion of Megakaryocyte-Specific Gata1 Loss on Megakaryopoiesis and the Hematopoietic Precursor Compartment.

Marjolein Meinders,Mark Hoogenboezem,Maaike R Scheenstra,Iris M De Cuyper,Petros Papadopoulos,Taco W Kuijpers,Tamás Németh,Timo K Van Den Berg,Laura Gutiérrez,Attila Mócsai,Kevin D Bunting

doi:10.1371/journal.pone.0154342

Marjolein Meinders, Mark Hoogenboezem + Show 9 more

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https://doi.org/10.1371/journal.pone.0154342

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Journal: PloS one	Publication Date: May 6, 2016
Citations: 12	License type: CC BY 4.0

Affiliation: University of Amsterdam, Semmelweis University

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.

Highlights

GATA1 is a critical transcription factor for the differentiation of several hematopoietic lineages [1]
These models were fundamental in identifying the critical role of Gata1 in megakaryopoiesis, they are not restricted to the megakaryocytic lineage or they pose a model for the downregulation of the expression levels of Gata1 without gene ablation
Comparable to the ΔneoΔHS and Gata1.05 mouse models, Gata1cKOMK mice show severe macrothrombocytopenia accompanied by platelet dysfunction, while in Gata1cKOMK mice the red blood cells and white blood cell counts are unaffected

Summary

Introduction

GATA1 is a critical transcription factor for the differentiation of several hematopoietic lineages [1] It is expressed in megakaryocytes [2], primitive and definitive erythroid cells [3], eosinophils [4], mast cells [5], dendritic cells [6] and Sertoli cells of the testis [7]. It belongs to the GATA family of zinc-finger transcription factors, which recognize the W(A/T)GATAR(A/G) DNA motif, and is located on the X-chromosome [8]. As an additional dimension of regulation, timely GATA1 levels during lineage commitment and differentiation are crucial for its proper action as master transcription regulator, and reciprocal regulation with the other hematopoietic GATA factors, such as GATA2 and GATA3, during lineage commitment and specification needs to be properly orchestrated [14,15,16,17,18]

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