title: Mouse prenatal platelet-forming lineages share a core transcriptional program but divergent dependence on MPL.
abstract: 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.
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and.
authors.forename: Kathryn S
authors.initials: KS
authors.lastname: Potts
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and.
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Sargeant
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and.
authors.forename: Caleb A
authors.initials: CA
authors.lastname: Dawson
authors.affiliation: Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.affiliation: Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia; and Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: Samir
authors.initials: S
authors.lastname: Taoudi
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000172:deficiency / Q000235:genetics; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D034061:Thrombopoiesis / Q000235:genetics*; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; C481270:Mpl protein, mouse; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; D053628:Receptors, Thrombopoietin