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

Development. 2017 Feb 15;144(4):601-611. doi: 10.1242/dev.139873. Epub 2017 Jan 13.

Abstract

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.

Keywords: Chondrogenesis; Limb; Patterning; RAR; Regeneration; Retinoic acid.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ambystoma mexicanum / physiology*
  • Animals
  • Body Patterning*
  • Bone and Bones / metabolism
  • Cell Differentiation
  • Extremities / physiology
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Homeostasis
  • Receptors, Retinoic Acid / metabolism*
  • Regeneration / physiology*
  • Retinoic Acid Receptor gamma
  • Transcriptome
  • Tretinoin / metabolism
  • X-Ray Microtomography

Substances

  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Tretinoin