Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs.
Development (Cambridge, England)
The Company of Biologists
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Aztekin, C., Hiscock, T. W., Gurdon, J., Jullien, J., Marioni, J., & Simons, B. (2021). Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs.. Development (Cambridge, England) https://doi.org/10.1242/dev.199158
Absence of a specialised wound epidermis is hypothesised to block limb regeneration in higher vertebrates. To elucidate the cellular and molecular determinants of this tissue, we performed single-cell transcriptomics in regeneration-competent, -restricted, and -incompetent Xenopus tadpoles. We identified apical-ectodermal-ridge (AER) cells as the specialised wound epidermis, and found that their abundance on the amputation plane correlates with regeneration potential and injury-induced mesenchymal plasticity. By using ex vivo regenerating limb cultures, we demonstrate that extrinsic cues produced during limb development block AER cell formation. We identify Noggin , a morphogen expressed in cartilage/bone progenitor cells, as one of the key inhibitors of AER cell formation in regeneration-incompetent tadpoles. Extrinsic inhibitory cues can be overridden by Fgf10 , which operates upstream of Noggin and blocks chondrogenesis. Together, these results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. <h4>One Sentence Summary</h4> Extrinsic cues associated with chondrogenic progression inhibit AER cell formation and restrict limb regeneration potential.
Wellcome Trust (101050/Z/13/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
WELLCOME TRUST (098357/Z/12/Z)
WELLCOME TRUST (105031/D/14/Z)
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External DOI: https://doi.org/10.1242/dev.199158
This record's URL: https://www.repository.cam.ac.uk/handle/1810/322075
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