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Development January 1, 2021; 148 (11):

Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs.

Aztekin C , Hiscock TW , Gurdon J , Jullien J , Marioni J , Simons BD .

Absence of a specialized wound epidermis is hypothesized to block limb regeneration in higher vertebrates. However, the factors preventing its formation in regeneration-incompetent animals are poorly understood. To characterize the endogenous molecular and cellular regulators of specialized wound epidermis formation in Xenopus laevis tadpoles, and the loss of their regeneration competency during development, we used single-cell transcriptomics and ex vivo regenerating limb cultures. Transcriptomic analysis revealed that the specialized wound epidermis is not a novel cell state, but a re-deployment of the apical-ectodermal-ridge (AER) programme underlying limb development. Enrichment of secreted inhibitory factors, including Noggin, a morphogen expressed in developing cartilage/bone progenitor cells, are identified as key inhibitors of AER cell formation in regeneration-incompetent tadpoles. These factors can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. These results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates.

PubMed ID: 34105722
PMC ID: PMC8217717
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bmp2 bmp3 bmp4 chrdl1 chrdl2 dkk1 dkk3 dll1 dll4 fgf10 fgf16 fgf20 fgf7 fgf8 fgf9 frzb hoxa10 jag1 jag2 lgr5 lhx9 nog piwil1 rspo2 sall4 sfrp1 sfrp5 slc39a12 tgfb1 tgfb2 tln2 wnt3a wnt5a zic2 zic5 znf750
GO keywords: regeneration [+]
Antibodies: Cdh1 Ab1 Ctnnb1 Ab5 GFP Ab16 Itgb1 Ab1 Nog Ab2 Tp63 Ab2

Article Images: [+] show captions