FOXL2 Regulation of Murine Follicle-Stimulating Hormone Beta Transcription in Primary and Immortalized Murine Gonadotrophs.
Notice bibliographique
Résumé
Follicle-stimulating hormone (FSH) regulates ovarian and testicular function. Impairments in FSH synthesis or action have profound effects on fertility. FSH is a heterodimeric glycoprotein composed of a common α and unique β subunit. The transforming growth factor β superfamily ligands, activins and inhibins, were identified based on their respective abilities to selectively stimulate and suppress FSH release from pituitary gonadotroph cells. Activins stimulate FSHβ subunit (Fshb) transcription, the rate-limiting step in mature FSH synthesis. We and others demonstrated that activin A regulates murine Fshb transcription in immortalized gonadotroph cells (LβT2), at least in part, via the actions of SMAD proteins and the forkhead transcription factor FOXL2. Here, we investigated FOXL2's role in endogenous Fshb expression in primary murine pituitary cells and defined a mechanism for SMAD/FOXL2 synergistic activation of the murine Fshb promoter. Pituitaries from adult "floxed" Foxl2 mice were dissociated and plated in primary culture. Cells were then incubated with control or Cre recombinase (Ad-Cre) encoding adenoviruses. Cells were efficiently transduced and the single exon Foxl2 locus successfully recombined. Activin A stimulated Fshb mRNA levels in control, but not Ad-Cre cultures. Basal Fshb expression, which is dependent on autocrine/paracrine activins, was also significantly impaired in Ad-Cre relative to control cultures. To define mechanisms of FOXL2 action, we used a combination of heterologous (HepG2) and homologous (LβT2) immortalized cell-based assays. In HepG2 cells, over-expressed FOXL2 synergized with SMADs 2, 3, and 4 to stimulate murine Fshb promoter-reporter activity. Moreover, the combination of FOXL2 and SMAD3 conferred activin-induction, which was otherwise absent in these (and other) heterologous cells. In LβT2 cells, SMAD3-induction of Fshb promoter activity or endogenous mRNA expression was dependent on endogenous FOXL2. FOXL2/SMAD synergy required binding of both FOXL2 and SMAD4 to DNA. Three putative forkhead binding elements (FBE) have been identified in the murine Fshb promoter. Of these, only the most proximal was absolutely required for activin A induction of promoter activity in homologous cells. Additionally, mutations in a SMAD binding element (SBE) adjacent to the proximal FBE abrogated activin A or FOXL2/SMAD3 induction of reporter activity. 5' to the composite SBE/FBE is a PBX1/PREP1 binding site previously thought to mediate activin A-induction of murine and ovine Fshb promoter-reporters. However, introduction of a 2 base pair mutation that impaired PBX1/PREP1 (but neither SMAD nor FOXL2) binding did not alter activin A-stimulated promoter activity in homologous cells. Taken together, these and previous data suggest a model in which activins stimulate formation of FOXL2-SMAD2/3/4 complexes, which bind to the proximal murine Fshb promoter to regulate its transcription. Within these complexes, FOXL2 and SMAD4 bind to adjacent cis-elements and SMAD3 brokers the physical interaction between the two. As this composite response element is highly conserved, our data suggest a general mechanism whereby activins may regulate and/or modulate Fshb transcription in mammals. This research was supported by operating funds from the Canadian Institutes of Health Research (MOP 89991) to D.J.B. D.J.B. and S.T. hold a Chercheur-boursier (Senior) and a doctoral fellowship, respectively, from the Fonds de la recherche en sante du Quebec. (poster)
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 | 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) | 0,000 | 0,000 |
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 tête enseignante, 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 ».