title: The zebrafish granulocyte colony-stimulating factors (Gcsfs): 2 paralogous cytokines and their roles in hematopoietic development and maintenance.
abstract: Granulocyte colony-stimulating factor (Gcsf) drives the proliferation and differentiation of granulocytes, monocytes, and macrophages (mφs) from hematopoietic stem and progenitor cells (HSPCs). Analysis of the zebrafish genome indicates the presence of 2 Gcsf ligands, likely resulting from a duplication event in teleost evolution. Although Gcsfa and Gcsfb share low sequence conservation, they share significant similarity in their predicted ligand/receptor interaction sites and structure. Each ligand displays differential temporal expression patterns during embryogenesis and spatial expression patterns in adult animals. To determine the functions of each ligand, we performed loss- and gain-of-function experiments. Both ligands signal through the Gcsf receptor to expand primitive neutrophils and mφs, as well as definitive granulocytes. To further address their functions, we generated recombinant versions and tested them in clonal progenitor assays. These sensitive in vitro techniques indicated similar functional attributes in supporting HSPC growth and differentiation. Finally, in addition to supporting myeloid differentiation, zebrafish Gcsf is required for the specification and proliferation of hematopoietic stem cells, suggesting that Gcsf represents an ancestral cytokine responsible for the broad support of HSPCs. These findings may inform how hematopoietic cytokines evolved following the diversification of teleosts and mammals from a common ancestor.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego School of Medicine, La Jolla, CA;
authors.forename: David L
authors.initials: DL
authors.lastname: Stachura
authors.forename: Ondrej
authors.initials: O
authors.lastname: Svoboda
authors.forename: Clyde A
authors.initials: CA
authors.lastname: Campbell
authors.forename: Raquel
authors.initials: R
authors.lastname: Espín-Palazón
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Lau
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Petr
authors.initials: P
authors.lastname: Bartunek
authors.forename: David
authors.initials: D
authors.lastname: Traver
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006413:Hematopoietic System / Q000196:embryology / Q000378:metabolism; D017403:In Situ Hybridization; D008024:Ligands; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D038042:Myelopoiesis / Q000235:genetics; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008024:Ligands; D008164:Luminescent Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D029961:Zebrafish Proteins; D016179:Granulocyte Colony-Stimulating Factor