A27 ERK/MAPK SIGNALING PROMOTES GOBLET CELL DIFFERENTIATION BY INHIBITING THE NOTCH PATHWAY
Bibliographic record
Abstract
Several mouse genetic models have suggested an important role for EGF, Wnt, BMP/TGFbeta and Notch signaling pathways in the renewal and differentiation of intestinal stem cells. EGF and its orthologs TGFalpha and epiregulin are factors regulating growth in epithelial tissues through activation of the RAS/RAF/MEK/ERK MAPK signaling pathway. Accordingly, in human and mouse intestines, ERK activity is predominantly found in progenitor cells in the transit-amplifying zone of the crypts where it is thought to control the proliferation/differentiation switch (Aliaga 1999). Indeed, we and others have reported that ERKs are selectively inactivated during absorptive cell differentiation hence supporting the hypothesis that these kinases must be shut down for the initiation of this differentiation process (Lemieux 2011). However, the role of ERK signaling in differentiation of the secretory cell lineage, particularly in Goblet cell differentiation remains to be elucidated. This study was therefore conducted to analyze the role of ERK/MAPK signaling in the differentiation of intestinal Goblet cells and to elucidate the molecular events involved in this possible regulation. Goblet cell number and differentiation were analyzed in three mouse models exhibiting sustained activation of ERK/MAPK signaling in intestinal epithelium: mice expressing oncogenic BRAFV600E in intestinal epithelial cells (IECs), mice expressing activated Shp2E76K mutant in IECs and mice knockout for Dusp6 (an inhibitor of ERK). Western blot, qPCR analyses and luciferase assays were performed in goblet-like cells LS174T treated or not with the MEK inhibitor CI-1040 (2 uM). Alcian blue staining in the colon of BRafV600E, Shp2E76K and Dusp6-/- mice reveal a marked increase in the number of Goblet cells in comparison to their control littermates. Interestingly, inhibition of MEK/ERK signaling with CI-1040 significantly reduces MUC2 transcript levels in LS174T cells. This decrease in MUC2 expression is associated with decreased transcriptional activity of KLF4 which is involve in Goblet cell terminal differentiation. Most interestingly, we found that inhibition of the MEK/ERK signaling activates the NOTCH pathway as visualized by an increased cleavage of NICD, the NOTCH intracellular domain, and expression of HES1, a target gene. This accumulation of NICD and HES1 can be prevent by gamma-secretase complex inhibition suggesting a NOTCH-dependent mechanism. Notably, qPCR analyses demonstrated an increased expression of the NOTCH ligands Delta-like 1 and Delta-like 4 in CI-1040-treated cells. Taking together, our results strongly suggest that RAF/MEK/ERK signaling pathway promotes Goblet cell differentiation by inhibiting the activation of NOTCH, a pathway known to inhibit the secretory cell fate. CIHRFRQS
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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".