Orphan Nuclear Receptors in Reproduction: Lessons from Tissue-Specific Knockout Mice.
Bibliographic record
Abstract
Nuclear receptors interact with specific regulatory sequences of DNA to modulate gene transcription. The orphan nuclear receptor, liver receptor homolog-1 (NR5A2) is expressed in the ovary, exclusively in granulosa and luteal cells. A transgenic mouse (Nr5a2f/f) bearing loxP sites flanking sequence of the third and fourth exons of the Nr5a2 gene was crossed with mice expressing Cre recombinase under the control of ovary and uterine specific promoters. Crossing the Nr5a2f/f mouse with the AmhrCre/+ mouse edits floxed genes in granulosa cells from primary follicles onward, while crossing with the tgCyp19-Cre mouse excises the floxed sequence in granulosa cells from follicles in the early antral to the periovulatory stages of development. Mating with PgrCre/+ mice deletes the sequence in granulosa cells following the signal for ovulation. Female offspring from all three conditional knockout (cKO) lines mated, but were infertile and in-depth analysis revealed that infertility had different causes in each model. The AmhrCre/+ cKO mouse was anovulatory, with excessive follicular estrogen accumulation, failure of cumulus expansion and reduced progesterone synthesis. Transcriptome analysis revealed >3000 genes were over or underexpressed at the time of expected ovulation. The tgCyp19-Cre cKO mouse also failed to ovulate, but appeared to develop a theca-derived corpus luteum. In PgrCre/+/Nr5a2f/f females, the deletion of Nr5a2 expression from the corpus luteum was first visible 4 h after ovulation and completed by 24 h. The effect was abrogation of progesterone synthesis and gestational failure. Embryos were normal and, with progesterone replacement, implanted, but progesterone did not rescue pregnancy. By PCR and immunohistochemistry, NR5A2 was shown to be expressed the uterine stroma of wild type mice at dpc 3-5, and ablated by dpc 5 in PgrCre/+/Nr5a2f/f mice. Its absence from the uterine stroma resulted in embryo crowding, decidualization failure, and compromised gestation. In all three models, Nr5a2 deletion resulted in deficiencies of expression of several genes, including Star, Cyp11a1, Hoxa10 and Wnt 4a, among others. We conclude that NR5A2 plays multiple, non-overlapping roles in reproductive processes, as it is essential for ovulation, luteal function and placental formation and function. (Supported by IRSC OGP 10118 to B.D.M.) (platform)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.005 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".