PUBLICATION
Exocrine pancreas proteases regulate β-cell proliferation in zebrafish ciliopathy models and in murine systems
- Authors
- Hostelley, T.L., Nesmith, J.E., Larkin, E., Jones, A., Boyes, D., Leitch, C.C., Fontaine, M., Zaghloul, N.A.
- ID
- ZDB-PUB-210616-19
- Date
- 2021
- Source
- Biology Open 10(6): (Journal)
- Registered Authors
- Zaghloul, Norann A.
- Keywords
- Ciliopathies, Diabetes, Zebrafish, β-cells
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Proliferation
- Chymotrypsin/genetics
- Chymotrypsin/metabolism
- Ciliopathies/etiology*
- Ciliopathies/metabolism*
- Ciliopathies/pathology
- Disease Susceptibility
- Gene Expression
- Insulin-Secreting Cells/metabolism*
- Mice
- Mutation
- Pancreas, Exocrine/enzymology*
- Peptide Hydrolases/genetics
- Peptide Hydrolases/metabolism*
- Zebrafish
- PubMed
- 34125181 Full text @ Biol. Open
Citation
Hostelley, T.L., Nesmith, J.E., Larkin, E., Jones, A., Boyes, D., Leitch, C.C., Fontaine, M., Zaghloul, N.A. (2021) Exocrine pancreas proteases regulate β-cell proliferation in zebrafish ciliopathy models and in murine systems. Biology Open. 10(6):.
Abstract
Pancreatic β-cells are a critical cell type in the pathology of diabetes. Models of genetic syndromes featuring diabetes can provide novel mechanistic insights into regulation of β-cells in the context of disease. We previously examined β-cell mass in models of two ciliopathies, Alström Syndrome (AS) and Bardet-Biedl Syndrome (BBS), which are similar in the presence of metabolic phenotypes, including obesity, but exhibit strikingly different rates of diabetes. Zebrafish models of these disorders show deficient β-cells with diabetes in AS models and an increased β-cells absent diabetes in BBS models, indicating β-cell generation or maintenance that correlates with disease prevalence. Using transcriptome analyses, differential expression of several exocrine pancreas proteases with directionality that was consistent with β-cell numbers were identified. Based on these lines of evidence, we hypothesized that pancreatic proteases directly impact β-cells. In the present study, we examined this possibility and found that pancreatic protease genes contribute to proper maintenance of normal β-cell numbers, proliferation in larval zebrafish, and regulation of AS and BBS β-cell phenotypes. Our data suggest that these proteins can be taken up directly by cultured β-cells and ex vivo murine islets, inducing proliferation in both. Endogenous uptake of pancreatic proteases by β-cells was confirmed in vivo using transgenic zebrafish and in intact murine pancreata. Taken together, these findings support a novel proliferative signaling role for exocrine pancreas proteases through interaction with endocrine β-cells.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping