Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis

Abstract

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1. a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1. b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1. aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1. aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1. b. We show that gfi1. aa and gfi1. b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1. aa and gfi1. b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1. aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1. b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1. b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1. aa and gfi1. b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors. © 2012 Elsevier Inc.