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Hif-1α and Hif-2α regulate hemogenic endothelium and hematopoietic stem cell formation in zebrafish.
- Source :
-
Blood [Blood] 2018 Mar 01; Vol. 131 (9), pp. 963-973. Date of Electronic Publication: 2018 Jan 16. - Publication Year :
- 2018
-
Abstract
- During development, hematopoietic stem cells (HSCs) derive from specialized endothelial cells (ECs) called hemogenic endothelium (HE) via a process called endothelial-to-hematopoietic transition (EHT). Hypoxia-inducible factor-1α (HIF-1α) has been reported to positively modulate EHT in vivo, but current data indicate the existence of other regulators of this process. Here we show that in zebrafish, Hif-2α also positively modulates HSC formation. Specifically, HSC marker gene expression is strongly decreased in hif -1aa;hif-1ab ( hif-1α ) and in hif-2aa;hif-2ab ( hif-2α ) zebrafish mutants and morphants. Moreover, live imaging studies reveal a positive role for hif-1α and hif-2α in regulating HE specification. Knockdown of hif-2α in hif-1α mutants leads to a greater decrease in HSC formation, indicating that hif-1α and hif-2α have partially overlapping roles in EHT. Furthermore, hypoxic conditions, which strongly stimulate HSC formation in wild-type animals, have little effect in the combined absence of Hif-1α and Hif-2α function. In addition, we present evidence for Hif and Notch working in the same pathway upstream of EHT. Both notch1a and notch1b mutants display impaired EHT, which cannot be rescued by hypoxia. However, overexpression of the Notch intracellular domain in ECs is sufficient to rescue the hif-1α and hif-2α morphant EHT phenotype, suggesting that Notch signaling functions downstream of the Hif pathway during HSC formation. Altogether, our data provide genetic evidence that both Hif-1α and Hif-2α regulate EHT upstream of Notch signaling.<br /> (© 2018 by The American Society of Hematology.)
- Subjects :
- Animals
Endothelium, Vascular cytology
Gene Expression Regulation genetics
Gene Knockdown Techniques
Hematopoietic Stem Cells cytology
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Receptors, Notch genetics
Zebrafish genetics
Endothelium, Vascular metabolism
Hematopoietic Stem Cells metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Receptors, Notch metabolism
Signal Transduction
Zebrafish metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 131
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 29339404
- Full Text :
- https://doi.org/10.1182/blood-2017-07-797795