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.
Highlights
In early vertebrate development, signaling molecules are required to direct individual cells as to when and where to commit to tissue-specific lineages and subsequently differentiate into their designated embryonic tissues
To define the molecular basis of low concentrations of Retinoic acid (RA) in myogenic differentiation, we examined the effects of arotinoid acid, a potent RA analog selective for RARs29, on myogenic conversion
We have examined the kinetics and molecular action of arotinoid acid, a retinoic acid receptors (RARs)-selective ligand, in myogenic conversion as compared to natural ligand RA
Summary
In early vertebrate development, signaling molecules are required to direct individual cells as to when and where to commit to tissue-specific lineages and subsequently differentiate into their designated embryonic tissues. While Myf[5] and MyoD initiate the expression of muscle-specific genes and commit the stem cells into skeletal muscle lineage, myogenin controls terminal differentiation including the fusion of myoblasts to myotubes[19,20,21]. Signaling is initiated following the activation of RARs by RA, which results in the recruitment of the transcriptional coactivator p300 and target gene expression[24,25,26] In this doctrine, RXR act as a silent partner since ligand activation is through the binding of RA to RAR. It is possible that the concentration-dependent effects of natural ligand RA on the differentiation of pluripotent stem cells may stem from a manifold of molecular mechanisms by affecting gene expression through pathways other than RAR selective signaling
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