Retinoic Acid Drives Aryl Hydrocarbon Receptor Expression and Is Instrumental to Dioxin-Induced Toxicity during Palate Development

Background: Palate development depends on complex events and is very sensitive to disruption. Accordingly, clefts are the most common congenital malformations worldwide, and a connection is proposed with fetal exposure to toxic factors or environmental contaminants, such as dioxins. There is increasing evidence that dioxin interferes with all-trans-retinoic acid (atRA), a hormone-like signal derived from vitamin A, which plays an essential role during embryonic development. Although similarities have been described between dioxin-induced toxicity and the outcome of altered atRA signaling during palate development, their relationship needs to be clarified

The Function of TIF2/GRIP1 in Mouse Reproduction Is Distinct from Those of SRC-1 and p/CIP

Human TIF2 (hTIF2) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 and p/CIP. Although the functions of hTIF2 and of its mouse homolog (GRIP1 or mTIF2) have been clearly established in vitro, their physiological role remains elusive. Here, we have generated mice lacking mTIF2/GRIP1 and examined their phenotype with a particular emphasis on reproductive functions. TIF2(−/−) mice are viable, but the fertility of both sexes is impaired. Male hypofertility is due to defects in both spermiogenesis (teratozoospermia) and age-dependent testicular degeneration, and TIF2 expression appears to be essential for adhesion of Sertoli cells to germ cells. Female hypofertility is due to a placental hypoplasia that most probably reflects a requirement for maternal TIF2 in decidua stromal cells that face the developing placenta. We conclude that TIF2 plays a critical role in mouse reproductive functions, whereas previous reports have not revealed serious fertility impairment in SRC-1(−/−) or p/CIP(−/−) mutants. Thus, even though the three p160 coactivators exhibit strong sequence homology and similar activity in assays in vitro, they play distinct physiological roles in vivo, as their genetic eliminations result in distinct pathologies

Retinoid X receptor beta (RXRB) expression in Sertoli cells controls cholesterol homeostasis and spermiation.

International audienceSomatic, targeted inactivation of the retinoid X receptor beta gene (Rxrb) in Sertoli cells (SC; yielding Rxrb(Ser-/-) mutants) leads to failure of spermatid release, accumulation of cholesterol esters and, subsequently, testis degeneration. These abnormalities are identical, in their nature and kinetics, to those observed upon inactivating Rxrb in the whole organism, thereby demonstrating that all reproductive functions of RXRB are carried out in SC. The Rxrb(Ser-/-) testis degeneration is a consequence of a cholesterol ester cell overload occurring in SC in response to reduced ABCA1- and SCARB1-mediated cholesterol efflux. The failure of spermiation was also reported in mice lacking the retinoic acid (RA) receptor-alpha (RARA) in SC (Rara(Ser-/-) mutants) and represents, in addition, a feature of vitamin A deficiency that can be readily induced in mice lacking the lecithin:retinol acyltransferase (Lrat(-/-) mutants). Altogether, these findings support the conclusion that RXRB heterodimerized with a RA-liganded RARA transduces signals required in SC for spermatid release

Somatic ablation of the Lrat gene in the mouse retinal pigment epithelium drastically reduces its retinoid storage.

PURPOSE: To generate a mouse model in which the Lrat gene is selectively disrupted in the retinal pigment epithelium (RPE). To evaluate the effects on the synthesis of retinyl esters and on the expression of other proteins involved in the continuation of the visual cycle. METHODS: A mouse line in which part of the first exon of the Lrat gene has been flanked by loxP sites, was generated and used in the study (Lrat(L3/L3) mice). Heterozygous mice (Lrat(+/L3)) were crossed with mice expressing Cre-recombinase under control of the tyrosinase-related protein-1 (Tyrp1) promoter, which is active selectively in melanin-synthesizing cells such as RPE cells. Accordingly, mice obtained from these crosses should display an RPE-specific disruption of the Lrat gene (Lrat(rpe-/-)). In addition, by crossing CMV-Cre transgenic mice with Lrat(L3/L3) animals, a germline null Lrat knockout (Lrat(L-/L-) mice) was generated. RNA and protein expression, endogenous retinoid levels, and electroretinogram (ERG) analyses were performed on Lrat(rpe-/-) and Lrat(L-)/(L-) mice, to determine the effects of Lrat disruption. Retinoid levels in nonocular tissues were also analyzed for comparison. RESULTS: Analysis of RPE tissues from Lrat(rpe-/-) mice showed absence of Lrat message, lack of Lrat protein expression and consequently a reduced light response in ERG recordings. In addition, RPE cells from Lrat(rpe-/-) showed a strong reduction in their ability to synthesize all-trans retinyl esters, whereas Lrat activity in other tissues known to process retinol was comparable to control Lrat(L3/L3) animals. The Lrat(L-/L-) mice showed no detectable Lrat message, lack of protein expression, and barely detectable ester formation in RPE cells or several other relevant tissues analyzed. CONCLUSIONS: Three Lrat mouse lines with genetic modifications were generated. The Lrat(L-)/(L-) mice displayed features similar to equivalent models previously reported by others. The second mouse line (Lrat(rpe-/-)) displayed loss of Lrat function only in the RPE. The third line possesses functional Lrat in all tissues, but part of the Lrat coding gene was flanked by loxP sites (Lrat(L3/L3)). This feature allows the disruption of this gene in any tissue of choice, by intercrossing with mice in which Cre-recombinase expression is driven by an appropriate tissue-specific promoter

Spermatogonia Differentiation Requires Retinoic Acid Receptor γ

International audienceVitamin A is instrumental to mammalian reproduction. Its metabolite, retinoic acid (RA), acts in a hormone-like manner through binding to and activating three nuclear receptor isotypes, RA receptor (RAR)α (RARA), RARβ, and RARγ (RARG). Here, we show that 1) RARG is expressed by A aligned (Aal) spermatogonia, as well as during the transition from Aal to A1 spermatogonia, which is known to require RA; and 2) ablation of Rarg, either in the whole mouse or specifically in spermatogonia, does not affect meiosis and spermiogenesis but impairs the Aal to A1 transition in the course of some of the seminiferous epithelium cycles. Upon ageing, this phenomenon yields seminiferous tubules containing only spermatogonia and Sertoli cells. Altogether, our findings indicate that RARG cell-autonomously transduces, in undifferentiated spermatogonia of adult testes, a RA signal critical for spermatogenesis. During the prepubertal spermatogenic wave, the loss of RARG function can however be compensated by RARA, as indicated by the normal timing of appearance of meiotic cells in Rarg-null testes. Accordingly, RARG- and RARA-selective agonists are both able to stimulate Stra8 expression in wild-type prepubertal testes. Interestingly, inactivation of Rarg does not impair expression of the spermatogonia differentiation markers Kit and Stra8, contrary to vitamin A deficiency. This latter observation supports the notion that the RA-signaling pathway previously shown to operate in Sertoli cells also participates in spermatogonia differentiation