PUBLICATION
Tmed10 deficiency results in impaired exocrine pancreatic differentiation in zebrafish larvae
- Authors
- Tao, Z., Yang, D., Ni, R.
- ID
- ZDB-PUB-230820-50
- Date
- 2023
- Source
- Developmental Biology 503: 43-52 (Journal)
- Registered Authors
- Keywords
- Exocrine pancreas development, Transmembrane p24 trafficking protein 10, Zebrafish, β-catenin, γ-secretase
- MeSH Terms
-
- Alzheimer Disease*
- Amyloid Precursor Protein Secretases/genetics
- Animals
- Larva
- Nucleocytoplasmic Transport Proteins*/metabolism
- Pancreas, Exocrine*/embryology
- Pancreas, Exocrine*/metabolism
- Zebrafish/genetics
- beta Catenin/genetics
- PubMed
- 37597605 Full text @ Dev. Biol.
Citation
Tao, Z., Yang, D., Ni, R. (2023) Tmed10 deficiency results in impaired exocrine pancreatic differentiation in zebrafish larvae. Developmental Biology. 503:43-52.
Abstract
Transmembrane p24 trafficking protein 10 (TMED10) is a conserved vesicle trafficking protein. It is dysregulated in Alzheimer disease and plays a pivotal role in the pathogenesis of Alzheimer disease. In addition to the brain, TMED10 is highly expressed in the exocrine pancreas; however, its biological functions and underlying mechanisms remain largely unknown. We studied reduced Tmed10 in zebrafish embryos by morpholino oligonucleotide knockdown and CRISPR-Cas9 mutagenesis. Tmed10-deficient embryos showed extensive loss of acinar mass and impaired acinar differentiation. TMED10 has been reported to have an inhibitory effect on γ-secretase. As one of the substrates of γ-secretase, membrane-bound β-catenin was significantly reduced in Tmed10-deficient embryos. Increased γ-secretase activity in wild-type embryos resulted in a phenotype similar to that of tmed10 mutants. And the mutant phenotype could be rescued by treatment with the γ-secretase inhibitor, N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester (DAPT). In addition, the reduced membrane-bound β-catenin was accompanied with up-regulated β-catenin target genes in Tmed10-deficient embryos. Overexpression of β-catenin signaling inhibitor Dickkopf-1 (DKK-1) could rescue the exocrine pancreas defects. Taken together, our study reveals that Tmed10 regulates exocrine pancreatic differentiation through γ-secretase. Reduced membrane-bound β-catenin, accompanied with hyperactivation of β-catenin signaling, is an important cause of exocrine pancreas defects in Tmed10-deficient embryos. Our study reaffirms the importance of appropriate β-catenin signaling in exocrine pancreas development. These findings may provide a theoretical basis for the development of treatment strategies for TMED10-related diseases.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping