Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

Matthew Nguyen, Pankhuri Singhal, Judith W. Piet, Sandra J. Shefelbine, Malcolm Maden, S. Randal Voss, James R. Monaghan

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Salamanders are capable of regenerating amputated limbs by generating a mass of lineage-restricted cells called a blastema. Blastemas only generate structures distal to their origin unless treated with retinoic acid (RA), which results in proximodistal (PD) limb duplications. Little is known about the transcriptional network that regulates PD duplication. In this study, we target specific retinoic acid receptors (RARs) to either PD duplicate (RA treatment or RARγ agonist) or truncate (RARβ antagonist) regenerating limbs. RARE-EGFP reporter axolotls showed divergent reporter activity in limbs undergoing PD duplication versus truncation, suggesting differences in patterning and skeletal regeneration. Transcriptomics identified expression patterns that explain PD duplication, including upregulation of proximal homeobox gene expression and silencing of distal-associated genes, whereas limb truncation was associated with disrupted skeletal differentiation. RARβ antagonism in uninjured limbs induced a loss of skeletal integrity leading to long bone regression and loss of skeletal turnover. Overall, mechanisms were identified that regulate the multifaceted roles of RARs in the salamander limb including regulation of skeletal patterning during epimorphic regeneration, skeletal tissue differentiation during regeneration, and homeostatic regeneration of intact limbs.

Original languageEnglish
Pages (from-to)601-611
Number of pages11
JournalDevelopment (Cambridge)
Issue number4
StatePublished - Feb 15 2017

Bibliographical note

Publisher Copyright:
© 2017. Published by The Company of Biologists Ltd.


  • Chondrogenesis
  • Limb
  • Patterning
  • RAR
  • Regeneration
  • Retinoic acid

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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