title: Hemogenic endothelium specification and hematopoietic stem cell maintenance employ distinct Scl isoforms.
abstract: Recent studies have shown that nascent hematopoietic stem cells (HSCs) derive directly from the ventral aortic endothelium (VAE) via endothelial to hematopoietic transition (EHT). However, whether EHT initiates from a random or predetermined subpopulation of VAE, as well as the molecular mechanism underlying this process, remain unclear. We previously reported that different zebrafish stem cell leukemia (scl) isoforms are differentially required for HSC formation in the ventral wall of the dorsal aorta. However, the exact stage at which these isoforms impact HSC development was not defined. Here, using in vivo time-lapse imaging of scl isoform-specific reporter transgenic zebrafish lines, we show that prior to EHT scl-β is selectively expressed in hemogenic endothelial cells, a unique subset of VAE cells possessing hemogenic potential, whereas scl-α is expressed later in nascent HSCs as they egress from VAE cells. In accordance with their expression, loss-of-function studies coupled with in vivo imaging analysis reveal that scl-β acts earlier to specify hemogenic endothelium, which is later transformed by runx1 into HSCs. Our results also reveal a previously unexpected role of scl-α in maintaining newly born HSCs in the aorta-gonads-mesonephros. Thus, our data suggest that a defined hemogenic endothelial population preset by scl-β supports the deterministic emergence of HSCs, and unravel the cellular mechanisms by which scl isoforms regulate HSC development.
authors.affiliation: State Key Laboratory of Molecular Neuroscience, Center of Systems Biology and Human Health, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, P.R. China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Zhen
authors.forename: Yahui
authors.initials: Y
authors.lastname: Lan
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.forename: Wenqing
authors.initials: W
authors.lastname: Zhang
authors.forename: Zilong
authors.initials: Z
authors.lastname: Wen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D055018:Hemangioblasts / Q000166:cytology* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D017403:In Situ Hybridization; D008297:Male; D018613:Microscopy, Confocal; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D029961:Zebrafish Proteins; C489367:tal1 protein, zebrafish
keywords: Hematopoietic stem cells; Hemogenic endothelium; Scl; Tal1; Zebrafish