Ontogeny drives stage-specific effects of a Gata1 mutation

The biography of an organism, including, for instance, its genetic background and exposure to environmental influences, determines the penetrance and expressivity of monogenic diseases between individuals. This also applies at the single-cell level. Interestingly, mature blood and immune cells originate from anatomically and temporally distinct stem and progenitor populations at different stages of development. Here we show that the ontogeny or progenitor origin of megakaryocytes determines their developmental trajectory at the cellular and transcriptional level. As a result, a mutation in the key transcription factor Gata1 dysregulates megakaryopoiesis in an ontogeny-specific manner causing a stage-specific disorder. Particularly, only early extraembryonic hematopoietic progenitors drive blast-like cell development leading to a transient accumulation of megakaryocytes in the fetus but not in the adult. Therefore, pediatric blood disorders may differ functionally from adult diseases due to changing progenitor sources of mature blood and immune cells throughout development. HighlightsO_LIFetal and adult megakaryopoiesis pass through distinct immunophenotypic stages C_LIO_LIOntogeny of megakaryocytes dictates their unique transcriptional trajectory C_LIO_LIProgenitor origin rather than the differentiation pathway determines the effect of mutant Gata1 C_LIO_LIBlock in maturation at the progenitor level causes the accumulation of yolk sac-derived megakaryocytes in the presence of mutant Gata1 C_LIO_LIMutant Gata1 drives blast cell formation exclusively in yolk sac-derived lineages C_LI