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.
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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.
The authors declare no competing financial interests.
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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
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