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Retinoic acid breakdown is required for proximodistal positional identity during axolotl limb regeneration

Author

Listed:
  • Timothy J. Duerr

    (Department of Biology
    Institute for Chemical Imaging of Living Systems)

  • Melissa Miller

    (Department of Biology)

  • Sage Kumar

    (Institute for Chemical Imaging of Living Systems)

  • Dareen Bakr

    (Department of Biology)

  • Jackson R. Griffiths

    (Department of Biology)

  • Aditya K. Gautham

    (Department of Biology)

  • Danielle Douglas

    (Department of Biology)

  • S. Randal Voss

    (Ambystoma Genetic Stock Center)

  • James R. Monaghan

    (Department of Biology
    Institute for Chemical Imaging of Living Systems)

Abstract

Regenerating limbs retain their proximodistal (PD) positional identity following amputation. This positional identity is genetically encoded by PD patterning genes that instruct blastema cells to regenerate the appropriate PD limb segment. Retinoic acid (RA) is known to specify proximal limb identity, but how RA signaling levels are established in the blastema is unknown. Here, we show that RA breakdown via CYP26B1 is essential for determining RA signaling levels within blastemas. CYP26B1 inhibition molecularly reprograms distal blastemas into a more proximal identity, phenocopying the effects of administering excess RA. We identify Shox as an RA-responsive gene that is differentially expressed between proximally and distally amputated limbs. Ablation of Shox results in shortened limbs with proximal skeletal elements that fail to initiate endochondral ossification. These results suggest that PD positional identity is determined by RA degradation and RA-responsive genes that regulate PD skeletal element formation during limb regeneration.

Suggested Citation

  • Timothy J. Duerr & Melissa Miller & Sage Kumar & Dareen Bakr & Jackson R. Griffiths & Aditya K. Gautham & Danielle Douglas & S. Randal Voss & James R. Monaghan, 2025. "Retinoic acid breakdown is required for proximodistal positional identity during axolotl limb regeneration," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59497-5
    DOI: 10.1038/s41467-025-59497-5
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    References listed on IDEAS

    as
    1. Eugeniu Nacu & Elena Gromberg & Catarina R. Oliveira & David Drechsel & Elly M. Tanaka, 2016. "FGF8 and SHH substitute for anterior–posterior tissue interactions to induce limb regeneration," Nature, Nature, vol. 533(7603), pages 407-410, May.
    2. Sergej Nowoshilow & Siegfried Schloissnig & Ji-Feng Fei & Andreas Dahl & Andy W. C. Pang & Martin Pippel & Sylke Winkler & Alex R. Hastie & George Young & Juliana G. Roscito & Francisco Falcon & Dunja, 2018. "The axolotl genome and the evolution of key tissue formation regulators," Nature, Nature, vol. 554(7690), pages 50-55, February.
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    4. Catarina R. Oliveira & Dunja Knapp & Ahmed Elewa & Tobias Gerber & Sandra G. Gonzalez Malagon & Phillip B. Gates & Hannah E. Walters & Andreas Petzold & Hernan Arce & Rodrigo C. Cordoba & Elaiyaraja S, 2022. "Tig1 regulates proximo-distal identity during salamander limb regeneration," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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