PUBLICATION
Wnt signaling inhibition by monensin results in a period of Hippo pathway activation during intestinal adaptation in zebrafish
- Authors
- Isani, M.A., Gee, K., Schall, K., Schlieve, C.R., Fode, A., Fowler, K.L., Grikscheit, T.C.
- ID
- ZDB-PUB-190322-12
- Date
- 2019
- Source
- American journal of physiology. Gastrointestinal and liver physiology 316(6): G679-G691 (Journal)
- Registered Authors
- Keywords
- cell proliferation, intestinal adaptation, monensin, wnt, zebrafish
- MeSH Terms
-
- Adaptation, Physiological
- Animals
- Cell Proliferation/physiology
- Humans
- Intestines/physiology*
- Monensin/pharmacology*
- Protein Serine-Threonine Kinases/metabolism*
- Proton Ionophores/pharmacology
- Short Bowel Syndrome/metabolism*
- Trans-Activators/metabolism*
- Up-Regulation
- Wnt Signaling Pathway*/drug effects
- Wnt Signaling Pathway*/physiology
- Zebrafish
- Zebrafish Proteins/metabolism*
- PubMed
- 30896968 Full text @ Am. J. Physiol. Gastrointest. Liver Physiol.
Citation
Isani, M.A., Gee, K., Schall, K., Schlieve, C.R., Fode, A., Fowler, K.L., Grikscheit, T.C. (2019) Wnt signaling inhibition by monensin results in a period of Hippo pathway activation during intestinal adaptation in zebrafish. American journal of physiology. Gastrointestinal and liver physiology. 316(6):G679-G691.
Abstract
Introduction Intestinal adaptation (IA) is a critical response to increase epithelial surface area after intestinal loss. Short bowel syndrome (SBS) may follow massive intestinal resection in human patients, particularly without adequate IA. We previously validated a model in zebrafish (ZF) that recapitulates key SBS pathophysiologic features. Previous RNA sequencing in this model identified upregulation of genes in the Wnt and Hippo pathways. We therefore sought to identify the timeline of increasing cell proliferation and the signaling that might underpin the epithelial remodeling of IA in SBS.
Methods SBS was created in a ZF model as previously reported and compared to sham fish with and without exposure to monensin, an ionophore that inhibits canonical Wnt signaling. Rescue of the monensin effects was attempted with a glycogen synthase kinase 3 (GSK3) inhibitor that activates wnt signaling, CHIR-99021. A timeline was constructed to identify peak cellular proliferation and the Wnt and Hippo pathways were evaluated.
Results Peak stem cell proliferation and morphological changes of adaptation were identified at 7 days. Wnt inhibition diminished IA at 2 weeks and resulted in activation of genes of the Wnt/β-catenin and YAP/Hippo pathway. Increased cytoplasmic YAP was observed in monensin-treated SBS fish. Genes of the WIP (WASP-interacting protein) pathway were elevated during Wnt blockade.
Conclusion Cellular proliferation and morphological changes accompany SBS even in attempted wnt blockade. Wnt/β-catenin, YAP/Hippo pathway and WIP pathway genes increase during wnt blockade. Further understanding of the effects of Wnt and YAP pathway signaling in proliferating stem cells might enrich knowledge of targets to assist IA.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping