Refined control of cell stemness allowed animal evolution in the oxic realm

Abstract

Animal diversification on Earth has long been presumed to be associated with the increasing extent of oxic niches. Here, we challenge that view. We start with the fact that hypoxia (<1–3% O2) maintains cellular immaturity (stemness), whereas adult stem cells continuously—and paradoxically—regenerate animal tissue in oxygenated settings. Novel insights from tumour biology illuminate how cell stemness nevertheless can be achieved through the action of oxygen-sensing transcription factors in oxygenated, regenerating tissue. We suggest that these hypoxia-inducible transcription factors provided animals with unprecedented control over cell stemness that allowed them to cope with fluctuating oxygen concentrations. Thus, a refinement of the cellular hypoxia-response machinery enabled cell stemness at oxic conditions and, then, animals to evolve into the oxic realm. This view on the onset of animal diversification is consistent with geological evidence and provides a new perspective on the challenges and evolution of multicellular life.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Environmental and biological oxygen thresholds and a simplified depiction of activation and degradation of HIFs.
Fig. 2: The appearance of HIF and EPO proteins in a phylogenetic tree of multicellularity.
Fig. 3: Hypothetical models of cell stemness control within multicellularity and refined stemness control in relation to atmospheric oxygen and animal diversification at the Precambrian–Cambrian boundary.

References

  1. 1.

    Knoll, A. H. & Carrol, S. B. Early animal evolution: emerging views from comparative biology and geology. Science 284, 2130–2137 (1999).

    Article  Google Scholar 

  2. 2.

    Nursall, J. R. Oxygen as a prerequisite to the origin of the metazoa. Nature 183, 1170–1172 (1959).

    Article  Google Scholar 

  3. 3.

    Buravkova, L. B., Andreeva, E. R., Gogvadze, V. & Zhivotovsky, B. Mesenchymal stem cells and hypoxia:where are we. Mitochondrion 19, 105–112 (2014).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Ivanovic, Z. Hypoxia or in situ normoxia: the stem cell paradigm. J. Cell. Physiol. 219, 271–275 (2009).

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Vaapil, M. et al. Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells. PLoS ONE 7, e46543 (2012).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  6. 6.

    Gezer, D., Vukovic, M., Soga, T., Pollard, P. J. & Kranc, K. R. Concise review: genetic dissection of hypoxia signaling pathways in normal and leukemic Stem cells. Stem Cells 32, 1390–1397 (2014).

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Pietras, A. et al. High levels of HIF-2α highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J. Pathol. 214, 482–488 (2008).

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Mohlin, S., Hamidian, A. & Påhlman, S. HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts. Neoplasia 15, 328–338 (2013).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  9. 9.

    Semenza, G. L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  10. 10.

    Haase, V. H. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 27, 41–53 (2013).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  11. 11.

    Holmquist-Mengelbier, L. et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell. 10, 413–423 (2006).

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Canfield, D. E. in Treatise on Geochemistry 2nd edn, Vol. 6 (eds Holland, H. D. & Turekian, K. K.) 197–216 (Elsevier, Oxford, 2014).

  13. 13.

    McKeown, S. R. Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response. Br. J. Radiol. 87, 20130676 (2014).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  14. 14.

    Gorr, T. et al. Hypoxia tolerance in animals: biology and application. Physiol. Biochem. Zool. 83, 733–752 (2010).

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hochachka, P. & Lutz, P. Mechanism, origin, and evolution of anoxia tolerance in animals. Comp. Biochem. Physiol. B 130, 435–459 (2001).

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Massabuau, J.-C. From low arterial- to low tissue-oxygenation strategy. An evolutionary theory. Resp. Physiol. 128, 249–261 (2001).

    CAS  Article  Google Scholar 

  17. 17.

    Mohyeldin, A., Garzón-Muvdi, T. & Quiñones-Hinojosa, A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell. Stem Cell. 7, 150–161 (2010).

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Munksgaard Persson, M. et al.HIF-2α expression is suppressed in SCLC cells, which survive in moderateand severe hypoxia when HIF-1α is repressed. Am. J. Pathol. 180, 494–504 (2012).

    Article  PubMed  Google Scholar 

  19. 19.

    Mentel, M. & Martin, W. Anaerobic animals from an ancient, anoxic ecological niche. BMC Biol. 8, 32 (2010).

    Article  PubMed Central  PubMed  Google Scholar 

  20. 20.

    Ivanovic, Z. & Vlaski-Lafarge, M. Anaerobiosis and Stemness: An Evolutionary Paradigm for Therapeutic Applications (Academic Press, Boston, 2016).

    Google Scholar 

  21. 21.

    Hochachka, P. W. Living Without Oxygen (Harvard Univ. Press, Cambridge, 1980).

    Google Scholar 

  22. 22.

    Biggart, M. J. & Boh, D. J. Effect of hypothermia and cardiac arrest on outcome of near-drowning accidents in children. J. Pediatr. 117, 179–183 (1990).

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Melvin, A. & Rocha, S. Chromatin as an oxygen sensor and active player in the hypoxia response. Cell. Signal. 24, 35–43 (2012).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  24. 24.

    Gaspar-Maia, A., Alajem, A., Meshorer, E. & Ramalho-Santos, M. Open chromatin in pluripotency and reprogramming. Nat. Rev. Mol. Cell. Biol. 12, 36–47 (2011).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  25. 25.

    Loenarz, C. et al. The hypoxia‐inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO Rep. 12, 63–70 (2011).

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Rytkönen, K. T., Williams, T. A., Renshaw, G. M., Primmer, C. R. & Nikinmaa, M. Molecular evolution of the metazoan PHD–HIF oxygen-sensing system. Mol. Biol. Evol. 28, 1913–1926 (2011).

    Article  PubMed  Google Scholar 

  27. 27.

    Graham, A. M. & Presnell, J. S. Hypoxia inducible factor (HIF) transcription factor family expansion, diversification, divergence and selection in eukaryotes. PLoS ONE 12, e0179545 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  28. 28.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Davies, P. & Lineweaver, C. Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors. Phys. Biol. 8, 015001 (2011).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  30. 30.

    Jögi, A. et al. Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc. Natl Acad. Sci. USA 99, 7021–7026 (2002).

    Article  PubMed Central  PubMed  Google Scholar 

  31. 31.

    Helczynska, K. et al. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res. 63, 1441–1444 (2003).

    CAS  PubMed  Google Scholar 

  32. 32.

    Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W. & McKnight, S. L. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes. Dev. 12, 3320–3324 (1998).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  33. 33.

    Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 15, 501–513 (2009).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  34. 34.

    Dahia, P. L. M. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat. Rev. Cancer 14, 108–119 (2014).

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Mohlin, S., Wigerup, C., Jögi, A. & Påhlman, S. Hypoxia, pseudohypoxia and cellular differentiation. Exp. Cell. Res. 356, 192–196 (2017).

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Salama, R. et al. Heterogeneous effects of direct hypoxia pathway activation in kidney cancer. PLoS. ONE 10, e0134645 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  37. 37.

    Wong, W. J., Richardson, T., Seykora, J. T., Cotsarelis, G. & Simon, M. C. Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J. Invest. Dermatol. 135, 454–461 (2015).

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Nilsson, H. et al. HIF-2α expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia. Exp. Cell. Res. 303, 447–456 (2005).

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Rouault-Pierre, K. et al. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell. Stem Cell. 13, 549–563 (2013).

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    To, K. K. W., Sedelnikova, O. A., Samons, M., Bonner, W. M. & Huang, L. E. The phosphorylation status of PAS‐B distinguishes HIF‐1α from HIF‐2α in NBS1 repression. EMBO J. 25, 4784–4794 (2006).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  41. 41.

    Covello, K. L. et al. HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 20, 557–570 (2006).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  42. 42.

    Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nat. Rev. Mol. Cell. Biol. 9, 285–296 (2008).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  43. 43.

    Marshall, C. R. Explaining the Cambrian “explosion” of animals. Annu. Rev. Earth Planet. Sci. 34, 355–384 (2006).

    CAS  Article  Google Scholar 

  44. 44.

    Fernàndez-Busquets, X. et al. Cell adhesion-related proteins as specific markers of sponge cell types involved in allogeneic recognition. Dev. Comp. Immunol. 26, 313–323 (2002).

    Article  PubMed  Google Scholar 

  45. 45.

    Money, N. P. Mushroom stem cells. Bioessays 24, 949–952 (2002).

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Hoffmann, F. et al. An anaerobic world in sponges. Geomicrobiol. J. 22, 1–10 (2005).

    Article  Google Scholar 

  47. 47.

    Juliano, C. & Wessel, G. Versatile germline genes. Science 329, 640–641 (2010).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  48. 48.

    Valentine, J. W., Collins, A. G. & Meyer, C. P. Morphological complexity increase in metazoans. Paleobiology 20, 131–142 (1994).

    Article  Google Scholar 

  49. 49.

    Rose, S. M. A hierarchy of self-limiting reactions as the basis of cellular differentiation and growth control. Am. Nat. 86, 337–354 (1952).

    Article  Google Scholar 

  50. 50.

    El Albani, A. et al. Large colonial organisms with coordinated growth in oxygenated environments 2.1 Gyr ago. Nature 466, 100–104 (2010).

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Waldbauer, J. R., Newman, D. K. & Summons, R. E. Microaerobic steroid biosynthesis and the molecular fossil record of Archean life. Proc. Natl Acad. Sci. USA 108, 13409–13414 (2011).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  52. 52.

    Crowe, S. A. et al. Atmospheric oxygenation three billion years ago. Nature 501, 535–538 (2013).

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Zhou, X. et al. Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase. Cancer Res. 70, 4214–4221 (2010).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  54. 54.

    Canfield, D. E. Oxygen: A Four Billion Year History (Princeton Univ. Press, Princeton, 2014).

    Google Scholar 

  55. 55.

    Marshall, C. R. Explaining the Cambrian “explosion” of animals. Annu. Rev. Earth Planet. Sci. 34, 355–384 (2006).

    CAS  Article  Google Scholar 

  56. 56.

    Shu, D. G. et al. Lower Cambrian vertebrates from south China. Nature 402, 42–46 (1999).

    CAS  Article  Google Scholar 

  57. 57.

    Finch, C. E. Longevity, Senescence, and the Genome (Univ. Chicago Press, Chicago, 1994).

    Google Scholar 

  58. 58.

    Saul, J. M. & Schwartz, L. Cancer as a consequence of the rising level of oxygen in the Late Precambrian. Lethaia 40, 211–220 (2007).

    Article  Google Scholar 

  59. 59.

    Stücker, M. et al. The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and epidermis. J. Physiol. 538, 985–994 (2002).

    Article  PubMed Central  PubMed  Google Scholar 

  60. 60.

    Vidal, G. & Nystuen, J. P. Micropaleontology, depositional environment, and biostratigraphy of the Upper Proterozoic Hedmark Group, Southern Norway. Am. J. Sci. 290, 170–211 (1990).

    Google Scholar 

  61. 61.

    Gee, H. Before the Backbone: Views on the Origin of the Vertebrates (Springer, Bury St Edmunds, 1996).

    Google Scholar 

  62. 62.

    Lee, J. et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 9, 391–403 (2006).

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Losick, V. P., Morris, L. X., Fox, D. T. & Spradling, A. Drosophila stem cell niches: a decade of discovery suggests a unified view of stem cell regulation. Dev. Cell. 21, 159–171 (2011).

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Biteau, B., Hochmuth, C. E. & Jasper, H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell. Stem Cell. 9, 402–411 (2011).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  65. 65.

    Parle, E., Dirks, J.-H. & Taylor, D. Bridging the gap: wound healing in insects restores mechanical strength by targeted cuticle deposition. J. R. Soc. Interf. 13, 20150984 (2016).

    Article  Google Scholar 

  66. 66.

    Wigglesworth, V. Wound healing in an insect (Rhodnius prolixus Hemiptera). J. Exp. Biol. 14, 364–381 (1937).

    CAS  Google Scholar 

  67. 67.

    May, R. M. How many species are there on Earth? Science 241, 1441–1449 (1988).

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Hoback, W. W. & Stanley, D. W. Insects in hypoxia. J. Insect Physiol. 47, 533–542 (2001).

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Harrison, J. et al. Responses of terrestrial insects to hypoxia or hyperoxia. Resp. Physiol. Neurobiol. 154, 4–17 (2006).

    CAS  Article  Google Scholar 

  70. 70.

    Punt, A. The respiration of insect. Physiol. Comp. Oecol. 2, 59–63 (1950).

    Google Scholar 

  71. 71.

    Hetz, S. K. & Bradley, T. J. Insects breathe discontinuously to avoid oxygen toxicity. Nature 433, 516–519 (2005).

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Frouz, J. The effect of nest moisture on daily temperature regime in the nests of Formica polyctena wood ants. Insect Soc. 47, 229–235 (2000).

    Article  Google Scholar 

  73. 73.

    Van Nerum, K. & Buelens, H. Hypoxia-controlled winter metabolism in honeybees (Apis mellifera). Comp. Biochem. Physiol. A 117, 445–455 (1997).

    Article  Google Scholar 

  74. 74.

    Sohal, R. S., Agarwal, S., Dubey, A. & Orr, W. C. Protein oxidative damage is associated with life expectancy of houseflies. Proc. Natl Acad. Sci. USA 90, 7255–7259 (1993).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  75. 75.

    Kloek, G., Ridgel, G. & Ralin, D. Survivorship and life expectancy of Drosophila melanogaster populations in abnormal oxygen-normal pressure regimes. Aviat. Space Environ. Med. 47, 1174–1176 (1976).

    CAS  Google Scholar 

  76. 76.

    Riisgård, H. U., Kittner, C. & Seerup, D. F. Regulation of opening state and filtration rate in filter-feeding bivalves (Cardium edule, Mytilus edulis, Mya arenaria) in response to low algal concentration. J. Exp. Mar. Biol. Ecol. 284, 105–127 (2003).

    Article  Google Scholar 

  77. 77.

    Clemens, S., Massabuau, J.-C., Meyrand, P. & Simmers, J. Changes in motor network expression related to moulting behaviour in lobster: role of moult-induced deep hypoxia. J. Exp. Biol. 202, 817–827 (1999).

    PubMed  Google Scholar 

  78. 78.

    Chung, J. S., Dircksen, H. & Webster, S. G. A remarkable, precisely timed release of hyperglycemic hormone from endocrine cells in the gut is associated with ecdysis in the crab Carcinus maenas. Proc. Natl Acad. Sci. USA 96, 13103–13107 (1999).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  79. 79.

    Pechenik, J. A. Biology of the Invertebrates (McGraw-Hill Higher Education, New York, 2010).

    Google Scholar 

  80. 80.

    Jónasdóttir, S. H., Visser, A. W., Richardson, K. & Heath, M. R. Seasonal copepod lipid pump promotes carbon sequestration in the deep North Atlantic. Proc. Natl Acad. Sci. USA 112, 12122–12126 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  81. 81.

    KiØrboe, T. Colonization of marine snow aggregates by invertebrate zooplankton: abundance, scaling, and possible role. Limnol. Oceanogr. 45, 479–484 (2000).

    Article  Google Scholar 

  82. 82.

    Tang, K. W., Glud, R. N., Glud, A., Rysgaard, S. & Nielsen, T. G. Copepod guts as biogeochemical hotspots in the sea: evidence from microelectrode profiling of Calanus spp. Limnol. Oceanogr. 56, 666–672 (2011).

    CAS  Article  Google Scholar 

  83. 83.

    Sperling, E. A., Halverson, G. P., Knoll, A. H., Macdonald, F. A. & Johnston, D. T. A basin redox transect at the dawn of animal life. Earth Planet. Sci. Lett. 371–372, 143–155 (2013).

    Article  Google Scholar 

  84. 84.

    Sperling, E. A. et al. Statistical analysis of iron geochemical data suggests limited late Proterozoic oxygenation. Nature 523, 451–454 (2015).

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Ryan, H. E., Lo, J. & Johnson, R. S. HIF‐1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  86. 86.

    Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes. Dev. 12, 149–162 (1998).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  87. 87.

    West, C. M., van der Wel, H. & Wang, Z. A. Prolyl 4-hydroxylase-1 mediates O2 signaling during development of Dictyostelium. Development 134, 3349–3358 (2007).

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Hughes, B. T. & Espenshade, P. J. Oxygen‐regulated degradation of fission yeast SREBP by Ofd1, a prolyl hydroxylase family member. EMBO J. 27, 1491–1501 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  89. 89.

    Fredlund, E., Ringnér, M., Maris, J. M. & Påhlman, S. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc. Natl. Acad. Sci. USA 105, 14094–14099 (2008).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  90. 90.

    Sperling, E. A., Knoll, A. H. & Girguis, P. R. The ecological physiology of Earth's second oxygen revolution. Annu. Rev. Ecol. Evol. Syst. 46, 215–235 (2015).

    Article  Google Scholar 

  91. 91.

    Gray, J. S., Wu, R. S.-s & Or, Y. Y. Effects of hypoxia and organic enrichment on the coastal marine environment. Mar. Ecol. Prog. Ser. 238, 249–279 (2002).

    Article  Google Scholar 

  92. 92.

    Gunda, V. G. & Janapala, V. R. Effects of dissolved oxygen levels on survival and growth in vitro of Haliclona pigmentifera (Demospongiae). Cell. Tissue Res. 337, 527–535 (2009).

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Levin, L. in Oceanography and Marine Biology: An Annual Review Vol. 41 (eds Gibson, R. N. & Atkinson, R. J. A.) 1–45 (Taylor & Francis, London, 2003).

  94. 94.

    Mole, D. R. et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J. Biol. Chem. 284, 16767–16775 (2009).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  95. 95.

    Schödel, J. et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117, e207–e217 (2011).

    Article  PubMed Central  PubMed  Google Scholar 

  96. 96.

    Talks, K. L. et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol. 157, 411–421 (2000).

    CAS  Article  PubMed Central  PubMed  Google Scholar 

  97. 97.

    Bracken, C. P. et al. Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J. Biol. Chem. 281, 22575–22585 (2006).

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Shen, C. & Kaelin, W. G. The VHL/HIF axis in clear cell renal carcinoma. Semin. Cancer Biol. 23, 18–25 (2013).

    CAS  Article  PubMed  Google Scholar 

  99. 99.

    Jochmanová, I., Yang, C., Zhuang, Z. & Pacak, K. Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction. J. Natl. Cancer Inst. 105, 1270–1283 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  100. 100.

    McNicol, A. M. Update on tumours of the adrenal cortex, phaeochromocytoma and extra‐adrenal paraganglioma. Histopathology 58, 155–168 (2011).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Beckman for expert technical assistance. We thank colleagues for helpful criticism and comments, in particular, M. Andersen, S. Bengtson, C. Bjerrum, D. Canfield, K. Hancke, D. Mills, K. Mitchell, S. Molin, A. Pietras, E. Pope Seyum, J. Robertson and I. Øra. This work was supported by the team at NordCEE and by grants from the Swedish Research Council (2015-04693), Danish National Research Foundation (Grant DNRF53), the ERC (Oxygen Grant 267233), the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Fru Berta Kamprad Foundation, Region Skåne and Skåne University Hospital research funds.

Author information

Affiliations

Authors

Contributions

E.U.H. initiated the study. E.U.H. and S.P. developed the concept and designed the experiments. E.U.H. and K.v.S. performed the experiments. E.U.H., K.v.S. and S.P. analysed the data and wrote the paper.

Corresponding author

Correspondence to Emma U. Hammarlund.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary text, Supplementary Table 1, Supplementary Figures and Supplementary References

Supplementary Dataset

Supplementary Tables 2 and 3a,b

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hammarlund, E.U., von Stedingk, K. & Påhlman, S. Refined control of cell stemness allowed animal evolution in the oxic realm. Nat Ecol Evol 2, 220–228 (2018). https://doi.org/10.1038/s41559-017-0410-5

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing