Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 211, Issue 5, Pages 909-927Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131065
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Funding
- National Institutes of Health (NIH) [R01CA122726]
- Federal Share of the Program Income earned by the Massachusetts General Hospital [C06 CA599267]
- NIH [R01HL075735, R01DK096034-01, S10OD012027, T32 2012D006265]
- American Society of Hematology
- Massachusetts General Hospital Executive Committee on Research (MGH ECOR) Fund for Medical Discovery award
- Deutsche Jose Carreras Leukamie-Stiftung e. V. [FIJC-09/ED, F 09/01]
- MGH ECOR Fund for Medical Discovery award
- Lady Tata Memorial Trust award
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The zinc finger transcriptional repressor Gfi-1b is essential for erythroid and megakaryocytic development in the embryo. Its roles in the maintenance of bone marrow erythropoiesis and thrombopoiesis have not been defined. We investigated Gfi-1b's adult functions using a loxP-flanked Gfi-1b allele in combination with a novel doxycycline-inducible Cre transgene that efficiently mediates recombination in the bone marrow. We reveal strict, lineage-intrinsic requirements for continuous adult Gfi-1b expression at two distinct critical stages of erythropoiesis and megakaryopoiesis. Induced disruption of Gfi-1b was lethal within 3 wk with severely reduced hemoglobin levels and platelet counts. The erythroid lineage was arrested early in bipotential progenitors, which did not give rise to mature erythroid cells in vitro or in vivo. Yet Gfi-1b(-/-) progenitors had initiated the erythroid program as they expressed many lineage-restricted genes, including Klf1/Eklf and Erythropoietin receptor. In contrast, the megakaryocytic lineage developed beyond the progenitor stage in Gfi-1b's absence and was arrested at the promegakaryocyte stage, after nuclear polyploidization, but before cytoplasmic maturation. Genome-wide analyses revealed that Gfi-1b directly regulates a wide spectrum of megakaryocytic and erythroid genes, predominantly repressing their expression. Together our study establishes Gfi-1b as a master transcriptional repressor of adult erythropoiesis and thrombopoiesis.
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