title: Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl.
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.
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Pankhuri
authors.initials: P
authors.lastname: Singhal
authors.affiliation: Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA.
authors.forename: Judith W
authors.initials: JW
authors.lastname: Piet
authors.affiliation: Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shefelbine
authors.affiliation: Department of Biology and UF Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Malcolm
authors.identifier: 0000-0001-7178-5309
authors.initials: M
authors.lastname: Maden
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY 40506, USA.|Spinal Cord and Brain Injury Research Center, University of Kentucky, College of Medicine, Lexington, KY 40506, USA.
authors.forename: S Randal
authors.initials: SR
authors.lastname: Voss
authors.affiliation: Department of Biology, Northeastern University, Boston, MA 02115, USA j.monaghan@neu.edu.
authors.forename: James R
authors.identifier: 0000-0002-6689-6108
authors.initials: JR
authors.lastname: Monaghan
mesh_terms: D000558:Ambystoma mexicanum / Q000502:physiology*; D000818:Animals; D019521:Body Patterning; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D005121:Extremities / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006706:Homeostasis; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D059467:Transcriptome; D014212:Tretinoin / Q000378:metabolism; D055114:X-Ray Microtomography; D000097768:Retinoic Acid Receptor gamma
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta
keywords: Chondrogenesis; Limb; Patterning; RAR; Regeneration; Retinoic acid