Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos.
Studies with embryonic explants and embryonic stem cells have suggested a role for Hedgehog (Hh) signaling in hematopoiesis. However, targeted deletion of Hh pathway components in the mouse has so far failed to provide in vivo evidence. Here we show that zebrafish embryos mutant in the Hh pathway or treated with the Hh signaling inhibitor cyclopamine display defects in adult hematopoietic stem cell (HSC) formation but not in primitive hematopoiesis. Hh is required in the trunk at three consecutive stages during vascular development: for the medial migration of endothelial progenitors of the dorsal aorta (DA), for arterial gene expression, and for the formation of intersomitic vessel sprouts. Interference with Hh signaling during the first two stages also interferes with HSC formation. Furthermore, HSC and DA formation also share Vegf and Notch requirements, which further distinguishes them from primitive hematopoiesis and underlines their close relationship during vertebrate development.
Gering
Martin
M
Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.
Patient
Roger
R
D000818:Animals; D019521:Body Patterning / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D053823:Hedgehog Proteins; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000633:toxicity; D015027:Zebrafish
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D014704:Veratrum Alkaloids; C000541:cyclopamine