Mouse prenatal platelet-forming lineages share a core transcriptional program but divergent dependence on MPL

• Published in: Blood Vol. 126; no. 6; pp. 807 - 816
• Main Authors: Potts, Kathryn S., Sargeant, Tobias J., Dawson, Caleb A., Josefsson, Emma C., Hilton, Douglas J., Alexander, Warren S., Taoudi, Samir
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2015
• Subjects: Animals; Blood Platelets - cytology; Blood Platelets - metabolism; Cell Differentiation; Cell Lineage - genetics; Embryonic Development - genetics; GATA1 Transcription Factor - deficiency; GATA1 Transcription Factor - genetics; Gene Deletion; Gene Expression Regulation, Developmental; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Megakaryocytes - cytology; Megakaryocytes - metabolism; Mice; Mice, Knockout; NF-E2 Transcription Factor, p45 Subunit - deficiency; NF-E2 Transcription Factor, p45 Subunit - genetics; Receptors, Thrombopoietin - genetics; Receptors, Thrombopoietin - metabolism; Thrombopoiesis - genetics; Transcription, Genetic; Yolk Sac - cytology; Yolk Sac - growth & development; Yolk Sac - metabolism
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-12-616607

The thrombopoietic environment of the neonate is established during prenatal life; therefore, a comprehensive understanding of platelet-forming cell development during embryogenesis is critical to understanding the etiology of early-onset thrombocytopenia. The recent discovery that the first platelet-forming cells of the conceptus are not megakaryocytes (MKs) but diploid platelet-forming cells (DPFCs) revealed a previously unappreciated complexity in thrombopoiesis. This raises important questions, including the following. When do conventional MKs appear? Do pathogenic genetic lesions of adult MKs affect DPFCs? What role does myeloproliferative leukemia virus (MPL), a key regulator of adult megakaryopoiesis, play in prenatal platelet-forming lineages? We performed a comprehensive study to determine the spatial and temporal appearance of prenatal platelet-forming lineages. We demonstrate that DPFCs originate in the yolk sac and then rapidly migrate to other extra- and intraembryonic tissues. Using gene disruption models of Gata1 and Nfe2, we demonstrate that perturbing essential adult MK genes causes an analogous phenotype in the early embryo before the onset of hematopoietic stem/progenitor cell-driven (definitive) hematopoiesis. Finally, we present the surprising finding that DPFC and MK commitment from their respective precursors is MPL independent in vivo but that completion of MK differentiation and establishment of the prenatal platelet mass is dependent on MPL expression. •Prenatal platelet-forming lineages are subject to common transcription factor controls despite distinct spatial and ancestral origins.•Platelet-forming lineage production is MPL-independent on emergence, but MPL is required in the late fetus for efficient thrombopoiesis.