title: Retinal dysplasia and degeneration in RARbeta2/RARgamma2 compound mutant mice.
abstract: The eye is the organ whose development is the most frequently altered in response to maternal vitamin A deficiency [VAD; Warkany, J. and Schraffenberger, S. (1946). Archs Ophthalmol. 35, 150-169]. With the exception of prenatal retinal dysplasia, all the ocular abnormalities of the fetal VAD syndrome are recapitulated in mouse mutants lacking either RARalpha and RARbeta2, RARalpha and RARgamma, RARgamma and RARbeta2, or RXRalpha [Lohnes, D., Mark, M., Mendelsohn, C., Dolle, P., Dierich, A., Gorry, P., Gansmuller, A. and Chambon, P. (1994) Development 120, 2723-2748; Mendelsohn, C., Lohnes, D., Décimo, D., Lufkin, T., LeMeur, M., Chambon, P. and Mark, M. (1994) Development 120, 2749-2771; Kastner, P., Grondona, J. Mark, M., Gansmuller, A., LeMeur, M., Décimo, D., Vonesch, J.L., Dollé, P. and Chambon, P. (1994) Cell 78, 987-1003], thus demonstrating that retinoic acid (RA) is the active vitamin A metabolite during prenatal eye morphogenesis. Whether retinoids are also involved in postnatal eye development could not be investigated, as VAD newborns are not viable and the above RAR double null mutants and RXRalpha null mutants died in utero or at birth. We report here the generation of viable RARbeta2/RARgamma2 double null mutant mice, which exhibit several eye defects. The neural retina of newborn RARbeta2gamma2 mutants is thinner than normal due to a reduced rate of cell proliferation, and from day 4 shows multiple foci of disorganization of its layers. These RARbeta2gamma2 mutants represent the first genetically characterized model of retinal dysplasia and their phenotype demonstrates that RARs, and therefore RA, are required for retinal histogenesis. The RARbeta2gamma2 retinal pigment epithelium (RPE) cells display histological and/or ultrastructural alterations and/or fail to express cellular retinol binding protein I (CRBPI). Taken altogether, the early onset of the RPE histological defects and their striking colocalisation with areas of the neural retina displaying a faulty laminar organization, a reduced neuroblastic proliferation, and a lack of photoreceptor differentiation and/or increased apoptosis, make the RPE a likely target tissue of the RARbeta2gamma2 double null mutation. A degeneration of the adult neural retina, which may similarly be secondary to a defective RPE, is also observed in these mutants, thus demonstrating an essential role of RA in the survival of retinal cells. Moreover, all RARbeta2gamma2 mutants display defects in structures derived from the periocular mesenchyme including local agenesis of the choroid and of the sclera, small eyelids, and a persistence of the primary mesenchymal vitreous body. A majority of the RARbeta2 single null mutants also exhibit this latter defect, thus demonstrating that the RARbeta2 isoform plays a unique role in the formation of the definitive vitreous body.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Grondona
authors.forename: P
authors.initials: P
authors.lastname: Kastner
authors.forename: A
authors.initials: A
authors.lastname: Gansmuller
authors.forename: D
authors.initials: D
authors.lastname: Décimo
authors.forename: P
authors.initials: P
authors.lastname: Chambon
authors.forename: M
authors.initials: M
authors.lastname: Mark
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division; D004247:DNA / Q000032:analysis; D005124:Eye Abnormalities / Q000235:genetics / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D018168:Receptors, Retinoic Acid / Q000032:analysis*; D012160:Retina / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics / Q000473:pathology*; D015792:Retinal Dysplasia / Q000235:genetics / Q000473:pathology*; D017299:Rod Opsins / Q000032:analysis; D014212:Tretinoin / Q000378:metabolism
chemical_list: D018168:Receptors, Retinoic Acid; D017299:Rod Opsins; D014212:Tretinoin; D004247:DNA