Stachura, D.L., Svoboda, O., Campbell, C.A., Espín-Palazón, R., Lau, R.P., Zon, L.I., Bartunek, P., and Traver, D. (2013) The zebrafish granulocyte colony-stimulating factors (Gcsfs): 2 paralogous cytokines and their roles in hematopoietic development and maintenance. Blood. 122(24):3918-28.
Granulocyte colony stimulating factor (Gcsf) drives the proliferation and differentiation of granulocytes, monocytes, and
macrophages (mψs) from hematopoietic stem and progenitor cells (HSPCs). Analysis of the zebrafish genome indicates the presence
of two 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 mψs, 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 (HSCs), 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.