Pattern of Ovarian Gene Expression and Estrous Cyclicity in Mouse Lacking Nr5a2 in Granulosa Cells of Antral Follicles.
Notice bibliographique
Résumé
The orphan nuclear receptor Nr5a2, also known as liver receptor homolog-1, has been shown to regulate several reproductive events in mice, including ovulation, luteinization and female fertility. Depletion of Nr5a2 specifically in granulosa cells of antral follicles using transgenic mice caused the formation of a non-functional luteal-like structure, low progesterone synthesis, irregular mating frequency, anovulation and infertility. Our objectives were to establish whether the above-mentioned female mice present normal estrous cyclicity, and to determine the basis of the failure in progesterone levels by gene expression analysis of the ovaries. We generated granulosa-specific knockout mice by crossing Nr5a2-floxed and cytochrome P450 aromatase (Cyp19) Cre mice (cKO, genotype: Nr5a2f/f; tgCyp19Cre/+). A group of cKO adult females (n=5) and the not-knockout littermates (CON; n=5) were evaluated daily by vaginal cytology to determine the phase of the estrous cycle. The cKO females presented normal cycles with a length of 4 to 5 days, in accordance to the pattern showed by the control group. Females were then housed with reproductively proven males, examined for copulatory plugs and euthanized 5.5 days post-coitum. Estradiol measurement in follicular fluid and in serum showed that there is no difference of levels between cKO and CON females. It was shown in a published study that excising Nr5a2 in granulosa cells of small follicles results in an abnormal prolonged estrus phase, due to reduced levels of nitric oxide synthase Nos3 mRNA, leading to increased intrafollicular estradiol levels. There was no difference in Nos3 mRNA abundance between the cKO and CON mice. By comparing cKO and CON levels we show that progesterone synthesis is affected by the lack of Nr5a2 through the downregulation of the steroidogenic acute regulatory protein, StAR (p<0.01), and scavenger receptor B 1, Scarb1 (p<0.01), but not of the cytochrome P450 side-chain cleavage, Cyp11a1 or Cyp19a1. This indicates that Nr5a2 is important for the regulation of the cholesterol transport genes, but not for the genes involved in cholesterol transformation during steroidogenesis in our conditional knockout mouse model. Moreover, the vascular endothelial growth factor A, Vegfa, an angiogenesis gene, showed a downregulation (p<0.05) in ovaries lacking Nr5a2 in granulosa cells of antral follicles, while Vegfb was not affected. The matrix metalloproteinase 2, Mmp2, a gene related to tissue remodeling, is upregulated (p<0.05) in cKO ovaries when compared to CON ovaries. In conclusion, the absence of Nr5a2 in antral follicles, does not impair normal estrous cyclicity nor reduce intrafollicular and serum levels of estradiol. We conclude that the transport of cholesterol into the cells and into the mitochondria appears to be the limiting factor for the functionality of the luteal-like structures found in the cKO ovaries. Further, Nr5a2 regulates different categories of genes, including steroidogenic, angiogenic and remodeling genes. Supported by CIHR Operating Grant OGP 11018. KB is supported by FQRNT PBEEE.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».