title: 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.
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cooney
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Hildick-Smith
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Shafizadeh
authors.forename: Paul F
authors.initials: PF
authors.lastname: McBride
authors.forename: Kelli J
authors.initials: KJ
authors.lastname: Carroll
authors.forename: Heidi
authors.initials: H
authors.lastname: Anderson
authors.forename: George C
authors.initials: GC
authors.lastname: Shaw
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Tamplin
authors.forename: Diana S
authors.initials: DS
authors.lastname: Branco
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Dalton
authors.forename: Dhvanit I
authors.initials: DI
authors.lastname: Shah
authors.forename: Clara
authors.initials: C
authors.lastname: Wong
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004843:Epistasis, Genetic; D004920:Erythropoiesis / Q000235:genetics; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006413:Hematopoietic System / Q000196:embryology / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029961:Zebrafish Proteins; C492589:gfi1ab protein, zebrafish