Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2749-2771 ◽  
Author(s):  
C. Mendelsohn ◽  
D. Lohnes ◽  
D. Decimo ◽  
T. Lufkin ◽  
M. LeMeur ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Respiratory Tract ◽  
Double Mutant ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptors ◽  
Urinary System ◽  
Developmental Abnormalities ◽  
Great Vessels ◽  
Multiple Abnormalities ◽  
Lower Digestive Tract

Compound null mutations of retinoic acid receptor (RAR) genes lead to lethality in utero or shortly after birth and to numerous developmental abnormalities. In the accompanying paper (Lohnes, D., Mark., M., Mendelsohn, C., Dolle, P., Dierich, A., Gorry, Ph., Gansmuller, A. and Chambon, P. (1994). Development 120, 2723–2748), we describe malformations of the head, vertebrae and limbs which, with the notable exception of the eye defects, were not observed in the offspring of vitamin A-deficient (VAD) dams. We report here abnormalities in the neck, trunk and abdominal regions of RAR double mutant mice, which include: (i) the entire respiratory tract, (ii) the heart, its outlow tract and the great vessels located near the heart, (iii) the thymus, thyroid and parathyroid glands, (iv) the diaphragm, (v) the genito-urinary system, and (vi) the lower digestive tract. A majority of these abnormalities recapitulate those observed in the fetal VAD syndrome described by Joseph Warkany's group more than fourty years ago [Wilson, J. G., Roth, C. B. and Warkany, J. (1953) Am. J. Anat., 92, 189–217; and refs therein]. Our results clearly demonstrate that RARs are essential for vertebrate ontogenesis and therefore that retinoic acid is the active retinoid, which is required at several stages of the development of numerous tissues and organs. We discuss several possibilities that may account for the apparent functional redundancy observed amongst retinoic acid receptors during embryogenesis.

Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2723-2748 ◽  
Author(s):  
D. Lohnes ◽  
M. Mark ◽  
C. Mendelsohn ◽  
P. Dolle ◽  
A. Dierich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Congenital Malformations ◽  
Double Mutant ◽  
Congenital Abnormalities ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptors ◽  
Acid Receptor ◽  
Null Mutants

Numerous congenital malformations have been observed in fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189–217]. Previous studies of retinoic acid receptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590–1594; Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643–658; Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., Lemeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225–7229; Mendelsohn, C., Mark, M., Dolle, P., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggesting either that there is a considerable functional redundancy among members of the RAR family during ontogenesis or that the RARs are not 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 RAR double mutants invariably died either in utero or shortly after birth and presented a number of congenital abnormalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in various RAR double mutant fetuses and are similar to those previously seen in VAD fetuses. Interestingly, we found further abnormalities not previously reported in VAD fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Roles of retinoic acid receptors in early embryonic morphogenesis and hindbrain patterning

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 2031-2038 ◽  
Author(s):  
Olivia Wendling ◽  
Norbert B. Ghyselinck ◽  
Pierre Chambon ◽  
Manuel Mark
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Axial Rotation ◽  
Retinoic Acid Receptors ◽  
Retinoic Acid Signaling ◽  
Wild Type ◽  
Pharyngeal Arches ◽  
Embryonic Morphogenesis ◽  
Null Mutants

Mutants mice carrying targeted inactivations of both retinoic acid receptor (RAR) α and RARγ (Aα/Aγ mutants) were analyzed at different embryonic stages, in order to establish the timing of appearance of defects that we previously observed during the fetal period. We show that embryonic day (E)9.5 Aα/Aγ embryos display severe malformations, similar to those already described in retinaldehyde dehydrogenase 2 null mutants. These malformations reflect early roles of retinoic acid signaling in axial rotation, segmentation and closure of the hindbrain; formation of otocysts, pharyngeal arches and forelimb buds; and in the closure of the primitive gut. The hindbrain of E8.5 Aα/Aγ embryos shows a posterior expansion of rhombomere 3 and 4 (R3 and R4) markers, but fails to express kreisler, a normal marker of R5 and R6. This abnormal hindbrain phenotype is strikingly different from that of embryos lacking RARα and RARβ (Aα/Aβmutants), in which we have previously shown that the territory corresponding to R5 and R6 is markedly enlarged. Administration of a pan-RAR antagonist at E8.0 to wild-type embryos cultured in vitro results in an Aα/Aβ-like hindbrain phenotype, whereas an earlier treatment at E7.0 yields an Aα/Aγ-like phenotype. Altogether, our data suggest that RARα and/or RARγ transduce the RA signal that is required first to specify the prospective R5/R6 territory, whereas RARβ is subsequently involved in setting up the caudal boundary of this territory.

Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo

1990 ◽  
Vol 10 (5) ◽  
pp. 2335-2340
Author(s):  
V Giguère ◽  
M Shago ◽  
R Zirngibl ◽  
P Tate ◽  
J Rossant ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mouse Embryo ◽  
Retinoic Acid Receptor ◽  
Limb Bud ◽  
Retinoic Acid Receptors ◽  
Amino Terminus ◽  
Mammalian Development ◽  
Teratogenic Effects ◽  
Pregnant Mice ◽  
Acid Administration

Retinoic acid is known to have profound effects on developmental processes. It has been implicated as a putative morphogen in the developing chick limb bud and regenerating amphibian limb blastema and has been demonstrated to have powerful teratogenic effects in mammals, including humans. Recently, three specific retinoic acid receptors (RARs), RAR alpha, -beta, and -gamma, were identified and shown to be members of the steroid receptor superfamily. We report the identification of a novel RAR gamma isoform, mRAR gamma B, which differs from the previously described mouse RAR gamma at its amino terminus. In addition, we show that both RAR gamma isoforms are expressed maximally at midgestation in structures known to be affected adversely by retinoic acid administration to pregnant mice. Multiple RAR isoforms, each of which may play a unique or combinatorial role as a regulator of mammalian development, are thus expressed in the mouse embryo.

scholarly journals 9-cis-retinoic acid is a natural antagonist for the retinoic acid receptor response pathway

1993 ◽  
Vol 295 (2) ◽  
pp. 343-346 ◽  
Author(s):  
C Carlberg ◽  
J H Saurat ◽  
G Siegenthaler
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptors ◽  
Dependent Manner ◽  
Receptor Response ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
X Receptors ◽  
Dose Dependent

The pleiotropic activities of retinoids are mediated by two types of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). All-trans-retinoic acid (RA) transcriptionally activates RARs, but not RXRs, whereas its natural stereoisomer, 9-cis-RA, is the ligand for RXRs. Here, we demonstrate that 9-cis-RA did not transcriptionally activate RARs, whereas in the presence of all-trans-RA the transactivation of RARs was inhibited in a dose-dependent manner by 9-cis-RA. RAR homodimer complexes were destabilized in vitro in the presence of 9-cis-RA. This suggests that 9-cis-RA may be a natural antagonist of all-trans-RA for binding to RAR complexes. The levels of 9-cis-RA may determine by which pathway the transcription of retinoid-responsive genes is modulated.

scholarly journals Identification of a novel isoform of the retinoic acid receptor gamma expressed in the mouse embryo.

1990 ◽  
Vol 10 (5) ◽  
pp. 2335-2340 ◽  
Author(s):  
V Giguère ◽  
M Shago ◽  
R Zirngibl ◽  
P Tate ◽  
J Rossant ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Mouse Embryo ◽  
Retinoic Acid Receptor ◽  
Limb Bud ◽  
Retinoic Acid Receptors ◽  
Amino Terminus ◽  
Mammalian Development ◽  
Teratogenic Effects ◽  
Pregnant Mice ◽  
Acid Administration

Retinoic acid is known to have profound effects on developmental processes. It has been implicated as a putative morphogen in the developing chick limb bud and regenerating amphibian limb blastema and has been demonstrated to have powerful teratogenic effects in mammals, including humans. Recently, three specific retinoic acid receptors (RARs), RAR alpha, -beta, and -gamma, were identified and shown to be members of the steroid receptor superfamily. We report the identification of a novel RAR gamma isoform, mRAR gamma B, which differs from the previously described mouse RAR gamma at its amino terminus. In addition, we show that both RAR gamma isoforms are expressed maximally at midgestation in structures known to be affected adversely by retinoic acid administration to pregnant mice. Multiple RAR isoforms, each of which may play a unique or combinatorial role as a regulator of mammalian development, are thus expressed in the mouse embryo.

scholarly journals Chromosomal Integration of Retinoic Acid Response Elements Prevents Cooperative Transcriptional Activation by Retinoic Acid Receptor and Retinoid X Receptor

2002 ◽  
Vol 22 (5) ◽  
pp. 1446-1459 ◽  
Author(s):  
Bruno Lefebvre ◽  
Céline Brand ◽  
Philippe Lefebvre ◽  
Keiko Ozato
Keyword(s):  
Retinoic Acid ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Histone Deacetylase Inhibitors ◽  
Early Stage ◽  
Retinoic Acid Receptor ◽  
Gene Promoter ◽  
Retinoic Acid Receptors ◽  
Response Elements ◽  
Histone Hyperacetylation

ABSTRACT All-trans-retinoic acid receptors (RAR) and 9-cis-retinoic acid receptors (RXR) are nuclear receptors known to cooperatively activate transcription from retinoid-regulated promoters. By comparing the transactivating properties of RAR and RXR in P19 cells using either plasmid or chromosomal reporter genes containing the mRARβ2 gene promoter, we found contrasting patterns of transcriptional regulation in each setting. Cooperativity between RXR and RAR occurred at all times with transiently introduced promoters, but was restricted to a very early stage (<3 h) for chromosomal promoters. This time-dependent loss of cooperativity was specific for chromosomal templates containing two copies of a retinoid-responsive element (RARE) and was not influenced by the spacing between the two RAREs. This loss of cooperativity suggested a delayed acquisition of RAR full transcriptional competence because (i) cooperativity was maintained at RAR ligand subsaturating concentrations, (ii) overexpression of SRC-1 led to loss of cooperativity and even to strong repression of chromosomal templates activity, and (iii) loss of cooperativity was observed when additional cis-acting response elements were activated. Surprisingly, histone deacetylase inhibitors counteracted this loss of cooperativity by repressing partially RAR-mediated activation of chromosomal promoters. Loss of cooperativity was not correlated to local histone hyperacetylation or to alteration of constitutive RNA polymerase II (RNAP) loading at the promoter region. Unexpectedly, RNAP binding to transcribed regions was correlated to the RAR activation state as well as to acetylation levels of histones H3 and H4, suggesting that RAR acts at the mRARβ promoter by triggering the switch from an RNA elongation-incompetent RNAP form towards an RNA elongation-competent RNAP.

Sign in / Sign up

Export Citation Format

Share Document