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Retinoic acid receptor (RAR) and retinoid X receptor (RXR) form heterodimers and regulate retinoidmediated gene expression. We studied binding of RXR-and RAR-selective ligands to the RXR-RAR heterodimer and subsequent transcription. In limited proteolysis analyses, both RXR and RAR in the heterodimer bound their respective ligands and underwent a conformational change in the presence of a retinoic acidresponsive element. In reporter analyses, the RAR ligand (but not the RXR ligand), when added singly, activated transcription, but coaddition of the two ligands led to synergistic activation of transcription. This activation required the AF-2 domain of both RXR and RAR. Genomic footprinting analysis was performed with P19 embryonal carcinoma cells, in which transcription of the RAR␤ gene is induced upon retinoid addition. Paralleling the reporter activation data, only the RAR ligand induced in vivo occupancy of the RAR␤2 promoter when added singly. However, at suboptimal concentrations of RAR ligand, coaddition of the RXR ligand increased the stability of promoter occupancy. Thus, liganded RXR and RAR both participate in transcription. Finally, when these ligands were tested for teratogenic effects on zebra fish and Xenopus embryos, we found that coadministration of the RXR and RAR ligands caused more severe abnormalities in these embryos than either ligand alone, providing biological support for the synergistic action of the two ligands.Transcriptional responses to retinoids are mainly controlled by two classes of nuclear hormone receptors, retinoic acid (RA) receptors (RARs) and retinoid X receptors (RXRs), which form heterodimeric complexes, bind to RA-responsive elements (RAREs), and regulate gene expression in a retinoiddependent manner (reviewed in references 12, 25, 29, 30, 45, 46, 50, 57 and 60). The RAR-RXR heterodimer is activated by a number of naturally occurring retinoids that bind to RXR and/or RAR with different affinities (26,43,57). For example, RARs bind both all-trans-and 9-cis-RA stereoisomers, whereas RXRs bind only 9-cis-RA (3,4,26,43). The presence of multiple retinoids that are differentially distributed in various tissues and differentially bind to RARs and RXRs suggests that retinoid-dependent gene regulation and its biological effects are highly complex. There may be additional complexities depending on whether RAR and RXR in the heterodimer exhibit differential activities in response to retinoids. Given the complexity in retinoid action, it is important to study how each receptor in the heterodimer acts in response to various retinoids. Ligand binding and transcriptional activity of RXR may raise additional issues, as RXR forms heterodimers with several other nuclear receptors that respond to nonretinoid ligands (such as the thyroid hormone and vitamin D). In these cases, some retinoids, by binding to RXR, may elicit a modulatory effect on other ligands (12,38,45). However, making this possibility less attractive, it has been proposed that RXR does not play an active role in transcripti...

A model of handedness incorporating both genetic and cultural processes is proposed, based on an evolutionary analysis, and maximum-likelihood estimates of its parameters are generated. This model has the characteristics that (i) no genetic variation underlies variation in handedness, and (ii) variation in handedness among humans is the result of a combination of cultural and developmental factors, but (iii) a genetic influence remains since handedness is a facultative trait. The model fits the data from 17 studies of handedness in families and 14 studies of handedness in monozygotic and dizygotic twins. This model has the additional advantages that it can explain why monozygotic and dizygotic twins and siblings have similar concordance rates, and no hypothetical selection regimes are required to explain the persistence of left handedness.

Histone acetylation is thought to have a role in transcription. To gain insight into the role of histone acetylation in retinoid-dependent transcription, we studied the effects of trichostatin A (TSA), a specific inhibitor of histone deacetylase, on P19 embryonal carcinoma cells. We show that coaddition of TSA and retinoic acid (RA) markedly enhances neuronal differentiation in these cells, although TSA alone does not induce differentiation but causes extensive apoptosis. Consistent with the cooperative effect of TSA and RA, coaddition of the two agents synergistically enhanced transcription from stably integrated RA-responsive promoters. The transcriptional synergy by TSA and RA required the RA-responsive element and a functional retinoid X receptor (RXR)͞retinoic acid receptor (RAR) heterodimer, both obligatory for RA-dependent transcription. Furthermore, TSA led to promoter activation by an RXR-selective ligand that was otherwise inactive in transcription. In addition, TSA enhanced transcription from a minimum basal promoter, independently of the RA-responsive element. Finally, we show that TSA alone or in combination with RA increases in vivo endonuclease sensitivity within the RA-responsive promoter, suggesting that TSA treatment might alter a local chromatin environment to enhance RXR͞RAR heterodimer action. Thus, these results indicate that histone acetylation inf luences activity of the heterodimer, which is in line with the observed interaction between the RXR͞RAR heterodimer and a histone acetylase presented elsewhere.