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Stimulation of erythropoiesis by inhibiting a new hematopoietic death receptor in transgenic zebrafish

Nature Cell Biology volume 2, pages 549–552 (2000)Cite this article

Production of red blood cells is under both positive and negative control, and dysregulation of either of these control systems may cause human diseases such as anaemia or leukaemia. Erythropoietin, a key positive regulator of erythropoiesis, promotes the proliferation and survival of immature erythroid precursors in vitro and in vivo1. Recent in vitro studies have shown that death receptors and their ligands may function as negative regulators of erythropoiesis2, although the physiological significance of this regulation has yet to be revealed. We have isolated a new death receptor, the zebrafish haematopoietic death receptor (ZH-DR), that is specifically expressed in zebrafish embryonic haematopoietic cells. Here we show that transgenic zebrafish expressing a dominant negative form of ZH-DR produce a surplus of erythroid cells. This study provides the first in vivo model of erythroid dysregulation caused by inhibition of a lineage-specific death receptor, and may influence our understanding of human diseases such as polycythaemia.

Human erythroid cells express several death receptors2,3, including tumour-necrosis-factor receptor one (TNF-1), Fas (also known as CD95 or APO-1), DR4 (or TRAIL receptor-1) and DR5 (or TRAIL receptor-2). Fas is expressed in human erythroid cells at most stages of maturation, whereas its ligand, FasL, is expressed only in more mature erythroblasts. In vitro, the interaction between Fas and FasL leads to activation of caspases that, in turn, cleave the erythroid-specific transcription factor GATA-1 (ref. 2), thereby negatively regulating erythropoiesis. GATA-1 has been shown to be essential for development of erythroid cells, and disruption of GATA-1 in mice induces erythroid progenitors to undergo apoptosis4,5. By screening a complementary DNA library constructed from purified GATA-1-positive cells of transgenic zebrafish embryos, we have identified a gene that encodes a protein containing the "death domain", a unique cytoplasmic domain shared by all previously identified death receptors6. On the basis of the structural and functional studies described here, we propose to name this gene ZH-DR.

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Figure 1: Sequence and haematopoietic expression of ZH-DR.
Figure 2: Functional analysis of ZH-DR.

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Acknowledgements

We thank S. Marty, B. Z. Yuan, J. Johnson and B. Moore for technical assistance, M. Weiss, D. Munn and members of our laboratories for discussions. This work was supported by grants from the NIH to S.L. (R01RR13227 and R01DK52355).

Correspondence and requests for materials should be addressed to S.L.

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  1. Qiaoming Long

    Present address: Loeb Health Research Institute at the Ottawa Hospital and Department of Medicine, University of Ottawa, Ottawa, Ontario, K1Y 4E9, Canada

  2. Qiaoming Long, Haigen Huang and Ebrahim Shafizadeh: These authors contributed equally to this work

Authors and Affiliations

  1. Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, 30912, Georgia, USA

    Qiaoming Long, Haigen Huang, Ebrahim Shafizadeh, Ningai Liu & Shuo Lin

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Long, Q., Huang, H., Shafizadeh, E. et al. Stimulation of erythropoiesis by inhibiting a new hematopoietic death receptor in transgenic zebrafish. Nat Cell Biol 2, 549–552 (2000). https://doi.org/10.1038/35019592

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