Targeted Overexpression of CKI-Insensitive Cyclin-Dependent Kinase 4 Increases Functional β-Cell Number Through Enhanced Self-Replication in Zebrafish
- Authors
- Li, M., Maddison, L.A., Crees, Z., and Chen, W.
- ID
- ZDB-PUB-130412-12
- Date
- 2013
- Source
- Zebrafish 10(2): 170-6 (Journal)
- Registered Authors
- Chen, Wenbiao, Li, Mingyu
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified/genetics
- Animals, Genetically Modified/growth & development
- Animals, Genetically Modified/metabolism
- Cell Count
- Cell Division
- Cyclin-Dependent Kinase 4/genetics*
- Cyclin-Dependent Kinase 4/metabolism
- Cyclin-Dependent Kinase Inhibitor Proteins/metabolism
- Fluorescent Antibody Technique
- Insulin/metabolism
- Insulin-Secreting Cells/cytology
- Insulin-Secreting Cells/metabolism*
- Larva/genetics
- Larva/growth & development
- Larva/metabolism
- Zebrafish/genetics*
- Zebrafish/growth & development
- Zebrafish/physiology
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 23544990 Full text @ Zebrafish
β-Cells of the islet of Langerhans produce insulin to maintain glucose homeostasis. Self-replication of β-cells is the predominant mode of postnatal β-cell production in mammals, with about 20% of rodent β cells dividing in a 24-hour period. However, replicating β-cells are rare in adults. Induction of self-replication of existing β-cells is a potential treatment for diabetes. In zebrafish larvae, β-cells rarely self-replicate, even under conditions that favor β-cell genesis such overnutrition and β-cell ablation. It is not clear why larval β-cells are refractory to replication. In this study, we tested the hypothesis that insufficient activity of cyclin-dependent kinase 4 may be responsible for the low replication rate by ectopically expressing in β-cells a mutant CDK4 (CDK4R24C) that is insensitive to inhibition by cyclin-dependent kinase inhibitors. Our data show that expression of CDK4R24C in β-cells enhanced β-cell replication. CDK4R24C also dampened compensatory β-cell neogenesis in larvae and improved glucose tolerance in adult zebrafish. Our data indicate that CDK4 inhibition contributes to the limited β-cell replication in larval zebrafish. To our knowledge, this is the first example of genetically induced β-cell replication in zebrafish.