RETINAL DYSPLASIA AND DEGENERATION IN RAR-BETA-2 RAR-GAMMA-2 COMPOUNDMUTANT MICE/

The eye is the organ whose development is the most frequently altered in response to maternal vitamin A deficiency [VAD; Warkany, J. and Sch raffenberger, S. (1946). Archs Ophthalmol. 35, 150-169]. With the exce ption of prenatal retinal dysplasia, all the ocular abnormalities of t he fetal VAD syndrome are recapitulated in mouse mutants lacking eithe r RAR alpha and RAR beta 2, RAR alpha and RAR gamma, RAR gamma and RAR beta 2 or RXR alpha [Lohnes, D., Mark, M., Mendelsohn, C., Dolle, P., Dierich, A., Gorry, P., Gansmuller, A. and Chambon, P. (1994) Develop ment 120, 2723-2748; Mendelsohn, C., Lohnes, D. Decimo, D., Lufkin, T. , LeMeur, M., Chambon, P. and Mark, M. (1994) Development 120, 2749-27 71; Kastner, P., Grondona, J. Mark, M., Gansmuller, A., LeMeur, M., De cimo, D., Vonesch, J.L., Dolle, P. and Chambon, P. (1994) Cell 78, 987 -1003], thus demonstrating that retinoic acid (RA) is the active vitam in A metabolite during prenatal eye morphogenesis. Whether retinoids a re also involved in postnatal eye development could not be investigate d, as VAD newborns are not viable and the above RAR double null mutant s and RXR alpha null mutants died in utero or at birth. We report here the generation of viable RAR beta 2/RAR gamma 2 double null mutant mi ce, which exhibit several eye defects. The neural retina of newborn RA R beta 2 gamma 2 mutants is thinner than normal due to a reduced rate of cell proliferation, and from day 4 shows multiple foci of disorgani zation of its layers. These RAR beta 2 gamma 2 mutants represent the f irst genetically characterized model of retinal dysplasia and their ph enotype demonstrates that RARs, and therefore RA, are required for ret inal histogenesis. The RAR beta 2 gamma 2 retinal pigment epithelium ( RPE) cells display histological and/or ultrastructural alterations and /or fail to express cellular retinol binding protein I(CRBPI). Taken a ltogether, the early onset of the RPE histological defects and their s triking colocalisation with areas of the neural retina displaying a fa ulty laminar organization, a reduced neuroblastic proliferation, and a lack of photoreceptor differentiation and/or increased apoptosis, mak e the RPE a likely target tissue of the RAR beta 2 gamma 2 double null mutation. A degeneration of the adult neural retina, which may simila rly be secondary to a defective RPE, is also observed in these mutants , thus demonstrating an essential role of RA in the survival of retina l cells. Moreover, all RAR beta 2 gamma 2 mutants display defects in s tructures derived from the periocular mesenchyme including local agene sis of the choroid and of the sclera, small eyelids, and a persistence of the primary mesenchymal vitreous body. A majority of the RAR beta 2 single null mutants also exhibit this latter defect, thus demonstrat ing that the RAR beta 2 isoform plays a unique role in the formation o f the definitive vitreous body.