Ligand-Dependent Regulation of Retinoic Acid Receptor   in Rat Testis: In Vivo Response to Depletion and Repletion of Vitamin A

Akmal, Karin M.

doi:10.1210/en.139.3.1239

Cited by 23 publications

(24 citation statements)

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“…Interestingly, in freshly isolated gonads RAR immunoreactivity was essentially restricted to the cytosolic compartment of the gonocytes. Based on previous observations that unbound or free RAR exists in the cytoplasm (35,47), these findings suggest that endogenous RA is low or absent at this time in fetal FIG. 4.…”

Section: Figsupporting

confidence: 59%

Segregation of Retinoic Acid Effects on Fetal Ovarian Germ Cell Mitosis Versus Apoptosis by Requirement for New Macromolecular Synthesis*

Morita

Tilly

1999

Endocrinology

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Retinoic acid (RA), a naturally occurring metabolite of vitamin A, plays an essential role in regulating cellular growth, differentiation, and death in a variety of tissues, particularly during fetal development. However, essentially nothing is known of the effects of RA on fetal gametogenesis. Using a recently validated system of culturing murine fetal ovaries, herein we sought to characterize the actions of RA on female germ cell proliferation and apoptosis during oogenesis. In the absence of trophic hormone support, approximately 90% of the oogonia and oocytes present in fetal ovaries at the start of culture underwent apoptosis over a 72 h culture period (P Ͻ 0.05), whereas provision of 0.01-1 M RA dose dependently maintained germ cell numbers. In fact, ovaries cultured with 0.1 M RA for 72 h possessed approximately 30% more oogonia and oocytes as compared with the preculture mean number (P Ͻ 0.05). Additional experiments, using in situ DNA 3Ј-end-labeling and cellular morphology to assess apoptosis coupled with 5-bromo-2Ј-deoxyuridine incorporation to assess proliferation, revealed that RA acts as both a mitogen and a survival factor for female germ cells. Furthermore, the ability of RA to stimulate germ cell proliferation in cultured fetal ovaries was completely suppressed (P Ͻ 0.05) by cotreatment with inhibitors of transcription (␣-amanitin, 0.1 g/ml) or protein synthesis (cycloheximide, 1.0 g/ ml), whereas RA-mediated suppression of germ cell apoptosis was not affected by cotreatment with either macromolecular synthesis inhibitor (P Ͼ 0.05). Moreover, cotreatment of fetal ovaries with 5 M LY294002, an inhibitor of phosphatidylinositol 3Ј-kinase, had no effect on RA-promoted germ cell maintenance (P Ͼ 0.05). By comparison, the antiapoptotic effects of insulin-like growth factor I on germ cells in cultured fetal ovaries were significantly attenuated by cotreating ovaries with LY294002 (P Ͻ 0.05) but not with ␣-amanitin or cycloheximide (P Ͼ 0.05). Importantly, the effect of RA on the female germ line was also observed in vivo because a single oral administration of 100 mg/kg RA to timed-pregnant female mice resulted in a significantly (P Ͻ 0.05) larger endowment of primordial oocytes in female offspring. That these actions were mediated, at least in part, by specific retinoid receptors was demonstrated by the finding of retinoic acid receptor protein in fetal female gonocytes, as assessed by immunohistochemical localization experiments. Collectively, these data indicate that RA can function, in vitro and in vivo, as a potent germ cell survival factor and mitogen during fetal oogenesis in the mouse. (Endocrinology 140: 2696 -2703, 1999)

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Section: Figsupporting

confidence: 59%

Segregation of Retinoic Acid Effects on Fetal Ovarian Germ Cell Mitosis Versus Apoptosis by Requirement for New Macromolecular Synthesis*

Morita

Tilly

1999

Endocrinology

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“…Generally, however, the RALDH1 and 2 mRNA expression patterns in testis from vitamin A-suf®cient rats were more limited than the expression patterns of CRBP and RoDH isozymes, and seemed similar to the expression pattern of RARa, which was most intense in germ cells (Kim and Griswold, 1990;Lufkin et al, 1993). Moreover, germ cells of vitamin A-suf®cient rats express CRBP, RoDH1, and RoDH2 mRNA much less intensely relative to Sertoli cell expression Schmitt and Ong, 1993;Zhai et al, 1997;Akmal et al, 1998). Similarly, undetectable RALDH mRNA expression in Sertoli cells of vitamin A-suf®cient rats was not expected, because Sertoli cells synthesize RA in vitro and in culture and express CRBP, RoDH1, and RoDH2 intensely (Porter et al, 1983;Kato et al, 1985;Rajan et al, 1990;Zhai et al, 1997).…”

Section: Discussionmentioning

confidence: 97%

Cellular expression of retinal dehydrogenase types 1 and 2: Effects of vitamin A status on testis mRNA

2001

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We examined expression of retinal dehydrogenase (RALDH) types 1 and 2 in liver and lung, and the effect of vitamin A status on testis expression by in situ hybridization. Liver expressed RALDH1 and RALDH2 only in stellate cells and hepatocytes, respectively. Lung expressed RALDH1 and RALDH2 throughout the epithelia of the airways, from the principal bronchi to the respiratory bronchiole. Vitamin A-sufficient rats expressed RALDH1 in spermatocytes, with less intense expression in spermatogonia and spermatids, and expressed RALDH2 in interstitial cells, spermatogonia, and spermatocytes. Neither Sertoli nor peritubular cells showed detectable RALDH1 or RALDH2 mRNA. Vitamin A deficiency produced a sevenfold increase in RALDH1 and a 70-fold decrease in RALDH2 mRNA in testis. In each case, the net change reflected extensive loss of germ cells, increased intensity of expression in residual germ cells, and expression in Sertoli and peritubular cells. Low-dose RA relatively early during vitamin A depletion supported spermatogenesis and affected expression of both RALDHs, but did not reinstate "vitamin A normal" expression patterns. These results show that: RALDH1 and RALDH2 have distinct mRNA expression patterns in multiple cell types in three vitamin A target tissues; RALDH expression occurs in cell types that express cellular retinol-binding protein and retinol dehydrogenase isozymes (except stellate cells, for which retinol dehydrogenase expression remains unknown); vitamin A deficiency and RA supplementation affects the loci and intensity of RALDH mRNAs in testis; and low-dose RA does not substitute completely for retinol. Overall, these data provide insight into the unique functions of RALDH1 and RALDH2 in retinoid metabolism.

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“…The absence of tRA leads to the loss of germ cells by sloughing of the advanced germ cells from the testis and apoptosis of the remaining primary spermatocytes [17][18][19][20]. The only germ cells remaining in the testis are the type A spermatogonia and preleptotene spermatocytes [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis1

Dufour

Bhattacharya

et al. 2003

Biology of Reproduction

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Peroxisome proliferators include a diverse group of chemicals, some of which have been demonstrated to be testicular toxicants. However, the mechanism by which peroxisome proliferators, such as phthalates, cause testicular damage is not clear. It is known that retinoic acid receptor alpha (RARalpha) and its retinoic acid ligand, the acid form of vitamin A, are required for spermatogenesis. It has been demonstrated that the absence of RARalpha gene or vitamin A in the animal leads to testis degeneration and sterility. Therefore, any compound that disrupts the action of vitamin A in the testis could potentially be damaging to male fertility. The current investigation examined a novel hypothesis that a mechanism of degeneration by peroxisome proliferators in the testis is due, in part, to disruption of the critical RARalpha signaling pathway. We show that peroxisome proliferators were able to disrupt the retinoic acid-induced nuclear localization of RARalpha and the retinoic acid-stimulated increase in transcriptional activity of a retinoic acid-responsive reporter gene in Sertoli cells. Concomitantly, peroxisome proliferators increased the nuclear localization of PPARalpha and the transcriptional activity of a peroxisome proliferator-responsive reporter gene in these cells. These results indicate that peroxisome proliferators can indeed shift the balance of nuclear localization for RARalpha and PPARalpha, resulting in deactivation of the critical RARalpha transcriptional activity in Sertoli cells.

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Ligand-Dependent Regulation of Retinoic Acid Receptor in Rat Testis: In Vivo Response to Depletion and Repletion of Vitamin A

Cited by 23 publications

References 0 publications

Segregation of Retinoic Acid Effects on Fetal Ovarian Germ Cell Mitosis Versus Apoptosis by Requirement for New Macromolecular Synthesis*

Segregation of Retinoic Acid Effects on Fetal Ovarian Germ Cell Mitosis Versus Apoptosis by Requirement for New Macromolecular Synthesis*

Cellular expression of retinal dehydrogenase types 1 and 2: Effects of vitamin A status on testis mRNA

Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis1

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