Disease relevance of Rarg

• Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice [1].
• In embryos with RA-induced spina bifida, RARbeta2 was expressed in the closed neural tube while RARgamma1 and RARgamma2 were expressed in the open caudal neuroepithelium [2].
• RAR gamma 2 mutants appeared normal, whereas RAR gamma mutants exhibited growth deficiency, early lethality, and male sterility due to squamous metaplasia of the seminal vesicles and prostate [3].

High impact information on Rarg

• Null mutant mice for retinoic acid receptor gamma 2 (RAR gamma 2) or all RAR gamma isoforms were generated [3].
• In the present report, we show that RAR gamma 1, one of the two predominant RAR gamma isoforms, can inhibit the activity of RAR gamma 2, RAR beta, and endogenous RAR on the beta RARE [4].
• Ablation of the gene for RARgamma (Rarg) rescues Cyp26a1-null mutant animals from caudal regression and embryonic lethality, thus demonstrating that CYP26A1 suppresses the RA-mediated downregulation of WNT3A and FGF8 signaling pathways by eliminating ectopic RA in gastrulating tail bud mesoderm [5].
• In eukaryotic cells, liganded RAR gamma 2/RXR alpha heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway [6].
• In contrast to Rarg mutants, retinoic acid (RA) treatment on embryonic day 10.5 of Hoxd4 single or Hoxd4;Rarg double mutants does not rescue normal development of C2 [7].

Biological context of Rarg

• The role of RAR alpha 1 and RAR gamma 2 AF-1 and AF-2 activation functions and of their phosphorylation was investigated during RA-induced primitive and parietal differentiation of F9 cells [8].
• In this study, we dissected the role of the RAR gamma 2 and RXR alpha partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation [6].
• Differentiation requires the action of the receptors for all trans, and 9cis-retinoic acid (RAR and RXR, respectively) and is accompanied by growth inhibition, changes in cell morphology, increased apoptosis, proteolytic degradation of the RARgamma2 receptor, and induction of target genes [9].

Anatomical context of Rarg

• Hoxd4 and Rarg interact synergistically in the specification of the cervical vertebrae [7].
• RAR gamma 1 mRNA was detected in 3T3-L1 cells but was not affected by RA treatment; however, RAR gamma 2 mRNA was strongly induced by RA [10].
• We show that, in F9 cells and in transfected COS-1 cells, the nuclear retinoid receptors, retinoic acid receptor gamma2 (RARgamma2), RARalpha1, and retinoid X receptor alpha1 (RXRalpha1) are degraded in a retinoic acid-dependent manner through the ubiquitin-proteasome pathway [11].

Other interactions of Rarg

• Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1 [5].
• We report here the generation of viable RARbeta2/RARgamma2 double null mutant mice, which exhibit several eye defects [1].

Analytical, diagnostic and therapeutic context of Rarg

• To circumvent this redundancy, the endogenous RARgamma2 allele was replaced with a ligand-binding RARgamma mutant (RARgammaE(305)) by gene targeting in mouse embryonic stem (ES) cells [12].

References