Characterization of the WNT/B-catenin signaling pathway in the development of mouse ovarian surface epithelium (MOSE) and follicular ovulatory capability
Bibliographic record
Abstract
Wnts are secreted extracellular signaling molecules that act locally to control diverse developmental processes such as cell fate specification, cell proliferation, and cell differentiation. Three WNT signaling pathways have been identified. The best characterized is the canonical or WNT/β-catenin signaling pathway. Recently, the WNT signaling pathway has been implicated in ovarian development and differentiation. However, little is known about the expression or role of β-catenin/Tcf-signaling activity within ovarian compartments. In order to aid in the ongoing pursuit of elucidating the mechanisms that govern ovarian differentiation and development, I explored the possible roles of the canonical WNT signaling pathway in the development of the ovarian surface epithelium (OSE) and follicular ovulatory capability. To examine canonical Wnt-signaling within the ovary, I utilized the Tcf-lacZ-reporter mice. In Manuscript I, I present a detailed spatio-temporal pattern of β-catenin/Tcf mediated expression in the OSE throughout development. Cells covering the indifferent gonad at E11.5 were β-catenin/Tcf signaling (lacZ-positive). With further development and sexual differentiation, lacZ staining was lost over the testis but maintained on embryonic ovaries. This staining became dispersed and the proportion of lacZ-positive OSE cells decreased to relative constancy when female mice reached maturity. FACS analyses revealed the lacZ-positive cell population exhibits cytoprotective mechanisms as indicated by enrichment within a side population. The results indicate that the mouse OSE is heterogeneous and may contain a population of progenitor cells. In Manuscript II, I investigated the molecular connection between β-catenin and Tcf-mediated lacZ activity and assessed whether β-catenin stabilization regulates β-catenin/Tcf-mediated gene expression and OSE proliferation. β-catenin was detected on the lateral membranes of ovarian epithelium. I demonstrated that treatment of OSE cells with Wnt agonist stabilized β-catenin but failed to induce β-catenin/Tcf-lacZ expression. Furthermore, E-cadherin expression was down-regulated and the proliferative potency of OSE cells increased. Of four ovarian cancers cell lines screened, only the HEY cell line demonstrated induction of luciferase reporter expression upon canonical WNT stimulation. These studies indicate that nuclear localization of β-catenin is insufficient for β-catenin/Tcf mediated gene expression in OSE cells, suggesting GSK-3β inhibition as a result of altered WNT signaling is of major importance in the control of epithelial-mesenchymal transition and cell proliferation leading to tumorigenesis. In Manuscript III, I investigated the role of the canonical WNT signaling pathway in the development of follicular ovulatory capability. Oocytes in primordial and primary follicles did not show active WNT signaling. β-catenin/Tcf-signaling was activated at the secondary follicle stage and the proportion of β-catenin/Tcf-signaling (lacZ-positive) follicles increased with follicular maturation. In contrast, the majority (>90%) of oocytes recovered from the oviducts at estrus and following hormone stimulation were lacZ-negative. The results indicate that the canonical WNT signaling pathway is active in growing oocytes and suggest that canonical WNT signaling may be involved in the development of follicular ovulatory capability and identifies non-ovulatory follicles.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| 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".