A28 SHP-1 REGULATES INTESTINAL EPITHELIUM HOMEOSTASIS BY CONTROLLING ACTIVATION OF BOTH PI3K/AKT AND WNT/β-CATENIN PATHWAYS
Bibliographic record
Abstract
Shp-1 is a tyrosine phosphatase highly expressed in hematopoietic cells and involved in the control of proliferation and differentiation. This phosphatase is also expressed at lower levels in epithelial cells such as intestinal epithelium. Our previous results showed that loss of epithelial Shp-1 leads to an intestinalomegaly associated with increased epithelial cell proliferation. We also noticed that the PI3K/Akt and Wnt/β-catenin pathways were both hyperactivated in IECs from these mice in comparison to controls (Leblanc Faseb J 2017). However, the role of Shp-1 in this epithelium still remains poorly characterized. So we wanted to determine the contribution of hyperactive PI3K/Akt pathway in these phenotypic alterations. To determine the contribution of hyperactive PI3K/Akt pathway, we generated mice with a specific deletion of Pten in IEC (PtenIEC-KO mice) and carefully compared their intestinal phenotype with Shp-1IEC-KO mice. Interestingly, both Shp-1IEC-KO and PtenIEC-KO mice develop similar intestinal phenotype: increased proliferation rate, intestinalomegaly and increased Goblet cell number. However, Paneth cell maturation is impaired in Shp-1IEC-KO mice but not in PtenIEC-KO mice. Indeed, decreased gene expression of Lyz1 and an expansion of intermediate cells are observed in Shp-1IEC-KO mice. Since Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts, we analyzed stem cell activity ex vivo, in enteroids isolated from Shp-1IEC-KO , PtenIEC-KO and their control littermates. Surprisingly, we observed striking difference in enteroid development: PtenIEC-KO enteroids grow very well and develop many protrusions in comparison to their respective controls. However, while proliferation is increased in Shp-1IEC-KO enteroids, their morphogenesis is clearly impaired; diminution of R-spondin in the culture medium rescues de novo crypt formation in Shp-1-deficient organoids. Our results indicate that loss of Shp-1 in IEC phenocopies many defects that are observed in PtenIEC-KO mice, including intestinalomegaly and abnormal Goblet cell differentiation. However, defects in Paneth cell maturation observed in Shp-1IEC-KO mice is probably triggered by the hyperactivation of Wnt/β-catenin signaling observed in these mice. NSERC
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".