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Function of the Retinoic Acid Receptors (Rars) During Development (I) Craniofacial and Skeletal Abnormalities in RAR Double Mutants

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Function of the Retinoic Acid Receptors (Rars) During Development (I) Craniofacial and Skeletal Abnormalities in RAR Double Mutants Development 120, 2723-2748 (1994) 2723 Printed in Great Britain © The Company of Biologists Limited 1994 Function of the retinoic acid receptors (RARs) during development (I) Craniofacial and skeletal abnormalities in RAR double mutants David Lohnes*,†, Manuel Mark*, Cathy Mendelsohn*,‡, Pascal Dollé, Andrée Dierich, Philippe Gorry, Anne Gansmuller and Pierre Chambon§ Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique de l’INSERM, Institut de Chimie Biologique, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France *Should be considered as equal first authors †Present address: Institut de recherches cliniques de Montréal, Laboratoire de Biologie Cellulaire et Moléculaire, 110 Avenue des Pins-Ouest, Montréal, Québec H2W 1R7, Canada ‡Present address: Columbia University, Department of Physiology and Biophysics, 630 W 168th Street, New York, NY 10032, USA §Author for correspondence SUMMARY Numerous congenital malformations have been observed in abnormalities, which are reported in this and in the accom- fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., panying study. We describe here multiple eye abnormali- Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189-217]. ties which are found in various RAR double mutant fetuses Previous studies of retinoic acid receptor (RAR) mutant and are similar to those previously seen in VAD fetuses. mice have not revealed any of these malformations [Li, E., Interestingly, we found further abnormalities not previ- Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) ously reported in VAD fetuses. These abnormalities affect Proc. Natl. Acad. Sci. USA 90, 1590-1594; Lohnes, D., ocular glands, salivary glands and their associated ducts, Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, the axial and limb skeleton, and all skeletal elements P. (1993) Cell 73, 643-658; Lufkin, T., Lohnes, D., Mark, derived from the mesectoderm of the frontonasal mass and M., Dierich, A., Gorry, P., Gaub, M. P., LeMeur, M., of the second and third pharyngeal arches. RAR double Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225- mutants also exhibit supernumerary cranial skeletal 7229; Mendelsohn, C., Mark, M., Dollé, P., Dierich, A., elements that are present in the ancestral reptilian skull. Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) The role of retinoic acid (RA) and of the RARs in the onto- Dev. Biol. in press], suggesting either that there is a con- genesis of the affected structures, particularly of those that siderable functional redundancy among members of the are derived from mesenchymal neural crest cells, is RAR family during ontogenesis or that the RARs are not discussed. essential transducers of the retinoid signal in vivo. In order to discriminate between these possibilities, we have generated a series of RAR compound null mutants. These Key words: retinoic acid, retinoic acid receptors, ontogenesis, neural RAR double mutants invariably died either in utero or crest, evolution, atavisms, mouse, homeotic transformations, eye, shortly after birth and presented a number of congenital skull, limb INTRODUCTION retinol excess, causing many developmental abnormalities, the precise malformation depending largely on the time of admin- It has long been known that retinol (vitamin A) is crucial for istration (reviewed in Morriss-Kay, 1993; Nau et al., 1994; normal growth, vision, reproduction, maintenance of numerous Hofman and Eichele, 1994). The spectacular effects of topical tissues and overall survival (Wolbach and Howe, 1925; see RA application on limb development and regeneration popu- Sporn et al., 1994 and Blomhoff, 1994, for reviews and refer- larized the belief that RA could in fact be a morphogen (for ences). Retinol is also essential for normal development, as reviews, see Tabin, 1991; Hofman and Eichele, 1994). shown by the appearance of multiple congenital abnormalities The discovery of a nuclear receptor for RA, acting as a in fetuses from dams fed a vitamin A-deficient (VAD) diet (the ligand-inducible transcriptional regulator (RAR; Petkovich et fetal VAD syndrome, see Wilson et al., 1953 and references al., 1987; Giguère et al., 1987), greatly advanced our under- therein). Interestingly, with the exception of vision (Wald, standing of the molecular mechanisms underlying the 1968), retinoic acid (RA) appears to be the active derivative of pleiotropic effects of retinoids (synthetic and natural derivatives vitamin A, since its administration can prevent or reverse most of RA; reviewed in Leid et al., 1992; Kastner et al., 1994; Man- of the defects induced by postnatal VAD (Thompson et al., gelsdorf et al., 1994; Linney and LaMantia, 1994). Since this 1964). Furthermore, RA excess is much more teratogenic than initial finding, it has been shown that the RA signal can be trans- 2724 D. Lohnes and others duced in cultured cells through two families of retinoid Taken together, the above findings suggest either that there receptors. The RAR family (RARα, β and γ and their isoforms) is a high degree of functional redundancy among members of are activated by both all-tr a n s RA and 9-ci s RA, whereas the the RAR family, or that the RARs are not essential transduc- RXR family (RXR α, β and γ) are activated only by 9-ci s RA . ers of the retinoid signal in vivo. To discriminate between these The DNA-binding and ligand-binding regions (regions C and possibilities, we have generated and analyzed RAR compound E, respectively) of the three RAR types are highly similar, null mutants. The defects displayed by various double mutants whereas the C-terminal F region and the central D region recapitulate essentially all of the congenital malformations exhibit little, if any, conservation. The three RAR types also found in fetal VAD. These double mutants also exhibit a diverge in their N-terminal B regions and further diversifica t i o n number of abnormalities not previously described in VAD is generated for each receptor type by variant isoforms differing experiments (see also the accompanying study). We report here in their N-terminal-most A regions (RARα1 and α2, β1 to β4, a detailed analysis of the craniofacial and skeletal defects and γ1 and γ2), which originate from alternate splicing and dif- found in RAR double null mutants. ferential promoter usage (reviewed in Leid et al., 1992). Amino acid sequence comparisons have revealed that the interspecies conservation of a given RAR type and of each of its isoforms MATERIALS AND METHODS is greater than the similarity found between the three RARs within a given species (see Kastner et al., 1994 for review). Fur- Generation of RAR double mutants α α β γ thermore, the various RAR isoforms contain two transcriptional The generation of RAR 1, , 2 and single null mutants has been activation functions (AFs), located in the N-terminal A/B region described (Lohnes et al., 1993; Lufkin et al., 1993; Mendelsohn et al., 1994a). Initial intercrosses of these single mutants were performed to (AF-1) and C-terminal E region (AF-2) which act synergisti- derive double heterozygotes. With the exception of RARα+/−/γ+/− cally, and sometimes differentially, to activate various RA- offspring, second generation animals were obtained by mating double responsive promoters. Taken together with the distinct spa- heterozygotes with the appropriate RAR heterozygous or homozy- tiotemporal transcript distribution observed for each RAR and gous single mutants to test for viability and fertility of compound isoforms during mouse embryogenesis and in adult tissues, the mutants. This was performed in order to optimize subsequent gener- above interspecies sequence conservation and transcriptional ation of double null mutants. The RAR double mutants and the crosses used to generate them were as follows: RARα1−/−/β2−/− were derived activation specificities suggested that each RAR isoform may − − − − perform unique functions (for refs see Kastner et al., 1994; from RARα1+/ /β2 / intercrosses or crosses between RARα1+/ / β2−/− and RARα1+/−/β2+/− animals; RARα−/−/β2−/− and RARα−/−/ Chambon, 1994). Furthermore, the finding that RA-responsive β +/− α+/− β −/− promoters are likely controlled in cultured cells through RAR- 2 mutants were derived from crosses between RAR / 2 males and RARα+/−/β2+/− or RARα+/−/β2−/− females; RARα1−/−/γ−/− RXR heterodimers (reviewed in Kastner et al., 1994; Mangels- mutants were derived from crossing RARα1−/−/γ+/− males and dorf et al., 1994; Chambon, 1994) suggested that the diverse RARα1+/−/γ+/− females; RARα1−/−/γ−/−/α2+/− mutants were derived effects of retinoids may also reside in the control of various from crosses between RARα1−/−/γ+/− and RARα+/−/γ+/− animals; subsets of retinoid-responsive promoters by different combina- RARα−/−/γ−/− mutants were obtained from intercrosses between tions of RAR-RXR types (and isoforms). RARα+/−/γ+/− animals; RARβ2−/−/γ−/− mutants were obtained To evaluate the function of the various RARs (types and from crosses between RARβ2−/−/γ+/− males and RARβ2+/−/γ+/− or − − − isoforms) in vivo, we have created mice lacking several of RARβ2 / /γ+/ females. these receptors. Surprisingly, mice deficient for RARα1 (Li et Matings and genotyping of offspring al., 1993; Lufkin et al., 1993), RARβ2 (Mendelsohn et al., 1994a) or RARγ2 (Lohnes et al., 1993) isoforms were appar- Animals were mated overnight and females examined for a vaginal plug the following morning. Noon of the day of evidence for a vaginal ently unaffected. In contrast, mice deficient for RARα or γ α γ plug was considered 0.5 dpc. Embryos (10.5-14.5 dpc) or 18.5 dpc RAR receptors (all or isoforms disrupted) exhibited post- fetuses were obtained by Cesarean section and genotypes determined partum lethality and growth deficiency (Lohnes et al., 1993; by genomic Southern blotting using DNA isolated from the yolk sac Lufkin et al., 1993). Furthermore, RARα null mice presented or placenta. Probes, digests and other conditions for southern blotting a degeneration of the testicular germinal epithelium, which was have been detailed elsewhere (Lohnes et al., 1993; Lufkin et al., 1993; similar to that observed in male rats maintained on a VAD diet Mendelsohn et al., 1994a).
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