Downregulation of RAR alpha in mice by antisense transgene leads to a compensatory increase in RAR beta and RAR gamma and development of lymphoma.

Retinoic acid receptors (RARs) alpha, beta, and gamma contain retinoic acid response elements (RAREs) in their promoter regions and respond to their own activation, thus forming an autoregulatory loop. We generated transgenic mice that expressed an antisense construct of the RAR alpha. Homozygous transgenic mice demonstrated 30% to 80% reduction in RAR alpha protein expression in various tissues. Unlike RAR alpha null mice generated by knockout, our antisense mice demonstrated significant compensatory increases in the expression of RAR beta and RAR gamma proteins. Coarse fur, male sterility, and low body weight were other abnormalities observed in these mice. Most importantly, lymphoma developed in 44% of our homozygous transgenic mice at an early stage of life. These data suggest that RAR alpha is necessary for appropriate response of the RAR beta and RAR gamma genes to physiologic changes and deregulation of the RAR alpha in transgenic mice, which resulted in upregulation of RAR beta and RAR gamma, can be associated with lymphomagenesis. Thus, the data support the hypothesis that a balance among the RARs is necessary for appropriate response to various homeostatic needs.