ZFIN ID: ZDB-PUB-130412-12
Targeted Overexpression of CKI-Insensitive Cyclin-Dependent Kinase 4 Increases Functional β-Cell Number Through Enhanced Self-Replication in Zebrafish
Li, M., Maddison, L.A., Crees, Z., and Chen, W.
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.