Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment, the haematopoietic niche, which regulates HSPC behaviour1,2. The location of this niche varies across species, but the evolutionary pressures that drive HSPCs to different microenvironments remain unknown. The niche is located in the bone marrow in adult mammals, whereas it is found in other locations in non-mammalian vertebrates, for example, in the kidney marrow in teleost fish. Here we show that a melanocyte umbrella above the kidney marrow protects HSPCs against ultraviolet light in zebrafish. Because mutants that lack melanocytes have normal steady-state haematopoiesis under standard laboratory conditions, we hypothesized that melanocytes above the stem cell niche protect HSPCs against ultraviolet-light-induced DNA damage. Indeed, after ultraviolet-light irradiation, unpigmented larvae show higher levels of DNA damage in HSPCs, as indicated by staining of cyclobutane pyrimidine dimers and have reduced numbers of HSPCs, as shown by cmyb (also known as myb) expression. The umbrella of melanocytes associated with the haematopoietic niche is highly evolutionarily conserved in aquatic animals, including the sea lamprey, a basal vertebrate. During the transition from an aquatic to a terrestrial environment, HSPCs relocated into the bone marrow, which is protected from ultraviolet light by the cortical bone around the marrow. Our studies reveal that melanocytes above the haematopoietic niche protect HSPCs from ultraviolet-light-induced DNA damage in aquatic vertebrates and suggest that during the transition to terrestrial life, ultraviolet light was an evolutionary pressure affecting the location of the haematopoietic niche.
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We thank D. Richardson at the Harvard Center for Biological Imaging for infrastructure and support; C. MacGillivray at the HSCRB Histology Core and Joyce LaVecchio at the HSCRB Flow Cytometry Core for technical assistance; E. van Italie in M. Kirschner’s laboratory and J. Cech in C. Peichel’s laboratory for providing Xenopus and stickleback samples; the Zebrafish Atlas (http://zfatlas.psu.edu/, NIH grant R24 RR017441, Jake Gittlen Cancer Research Foundation, and PA Tobacco Settlement Fund) for provision of the adult zebrafish histology image. Any use of trade, product or firm names is for descriptive purposes only and does not imply endorsement by the US Government. This work was supported by HHMI and NIH grants 5P01 CA163222, R01 HL048801, P01 HL032262, U54 DK110805-01, R01 DK053298, U01 HL100001-05, and R24 DK092760 to L.I.Z. D.E.F. acknowledges grant support from NIH (5P01 CA163222 and 2R01 AR043369) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. E.J.H. was supported by 1K01DK111790-01. Further support came from the German Research Foundation (DFG-SFB850-A1, to W.D.) and the Excellence Initiative of the German Federal and State Governments (Centre for Biological Signalling Studies EXC 294, to W.D.). F.G.K. was supported by a postdoctoral fellowship of the German Cancer Aid (70110820), a return scholarship of the Forschungskommission, Faculty of Medicine, University of Freiburg, and an EXCEL-Fellowship of the Faculty of Medicine, University of Freiburg, funded by the Else-Kröner-Fresenius-Stiftung. N.S.J. was supported by the Great Lakes Fishery Commission. E.T. was supported by funding from Max Planck Gesellschaft and a Marie Curie Career Integration grant (631432), a Fritz Thyssen Stiftung and the DFG founded Research Training Group GRK2344 ‘MeInBio – BioInMe’. L.A.O. was supported by a Bauer Fellowship from Harvard University. J.M.G. was supported by T32 training grants (T32CA009172-39 and T32HL116324-03).
Nature thanks I. Beerman, G. Litman and S. Morrison for their contribution to the peer review of this work.