Activin A induction of FSHβ subunit transcription requires SMAD4 in immortalized gonadotropes
Bibliographic record
Abstract
Activins regulate FSH synthesis by stimulating the phosphorylation and nuclear accumulation of SMAD2 and SMAD3, which bind to a consensus SMAD-binding element in the proximal murine FSHbeta (Fshb) subunit gene to drive transcription. Previous over-expression and in vitro DNA binding analyses suggested that SMAD4 participates in complexes with SMAD2 and SMAD3 to regulate Fshb expression. Here, we have characterized the role of endogenous SMAD4 in activin A induction of Fshb transcription in immortalized murine gonadotropes (LbetaT2). We identified five murine Smad4 mRNA isoforms, of which, four are newly described; however, the canonical full-length form predominated at both the mRNA and protein levels. Depletion of endogenous SMAD4 by RNA interference (RNAi) abolished activin A-induced Fshb promoter-reporter activity and greatly attenuated constitutively active activin type IB receptor-stimulated Fshb mRNA levels. The activin A response was rescued with an RNAi-resistant form of wild-type SMAD4, but not with a DNA-binding-deficient (Lys88Arg) SMAD4, suggesting that DNA binding by SMAD4 is necessary for activin induction of the Fshb gene. Though SMAD2 and SMAD3 are generally thought to partner with SMAD4 prior to accumulation in the nucleus, treatment with leptomycin B, an inhibitor of SMAD4 nuclear export, reduced but did not prevent activin A induction of Fshb mRNA levels or promoter activity. In addition, a constitutively nuclear form of SMAD4 rescued the effect of endogenous SMAD4 depletion. Collectively, these data demonstrate a necessary role for SMAD4 in activin A induction of the murine Fshb gene in immortalized gonadotropes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".