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, Gfi1a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1b. We show that gfi1aa and gfi1b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1aa and gfi1b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1aa and gfi1b 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.

Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

“…Gfi1 has been demonstrated to be critical for haemogenic endothelium by repressing endothelial markers 8 . Since gfi1 is expressed at the aorta-gonad-mesonephros (AGM) region 36 and is sufficient for HSC development (Supplementary Fig. 6b), we overexpressed gfi1 to rescue the increased endothelial identity in erk2-overexpressed embryos.…”

GFI1B, EVI5, MYB—Additional genes that cooperate with the human BCL6 gene to promote the development of lymphomas

“…All of these have been recognized as proto-oncogenes [13–15]. Two ( GFI1B and MYB ) are transcription factors [16,17] and the third ( EVI5 ) is considered an essential regulator of cell membrane trafficking [18,19]. Additionally, immunohistochemistry performed on B- and T-cell human lymphomas (16 in the case of GFI1B, 27 for EVI5, 25 for MYB), both BCL6-positive and negative, confirmed our observations in murine lymphomas at the RNA and protein level: GFI1B and EVI5 are downregulated in BCL6-positive lymphomas as compared with BCL-negative tumors, and MYB can be either up- or down-regulated in BCL6-positive lymphomas as compared with BCL-negative controls.…”

A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia

“…For gene validation experiments, zebrafish embryo morphants were prepared and analyzed as previously described with o-dianisidine staining and flow cytometry. 7 Basal respiration, adenosine triphosphate production, and respiratory capacity of primary patient fibroblasts were assayed on a Seahorse XF96 Extracellular Flux Analyzer using the Mitochondrial Stress Test kit. Intact mitochondria were isolated from patient fibroblasts and K562 cell lines, and respiratory complex (RC) activity and assembly were determined using standard There is an Inside Blood Commentary on this article in this issue.…”