Implication of retinoic acid receptor selective signaling in myogenic differentiation

Abstract

Signaling molecules are important for committing individual cells into tissue-specific lineages during early vertebrate development. Retinoic acid (RA) is an important vertebrate morphogen, in that its concentration gradient is essential for correct patterning of the vertebrate embryo. RA signaling is mediated through the activation of retinoic acid receptors (RARs), which function as ligand-dependent transcription factors. In this study, we examined the molecular mechanisms of RAR-selective signaling in myogenic differentiation. We found that just like natural ligand RA, a RAR-selective ligand is an effective enhancer in the commitment of skeletal muscle lineage at the early stage of myogenic differentiation. Interestingly, the kinetics and molecular basis of the RAR-selective ligand in myogenic differentiation are similar to that of natural ligand RA. Also similar to natural ligand RA, the RAR-selective ligand enhances myogenic differentiation through β-catenin signaling pathway while inhibiting cardiac differentiation. Furthermore, while low concentrations of natural ligand RA or RAR-selective ligand regulate myogenic differentiation through RAR function and coactivator recruitment, high concentrations are critical to the expression of a model RA-responsive gene. Thus our data suggests that RAR-mediated gene regulation may be highly context-dependent, affected by locus-specific interaction or local chromatin environment.