Targeted overexpression of CKI-insensitive cyclin-dependent kinase 4 increases functional β-cell number through enhanced self-replication in zebrafish.

Li M, Maddison LA, Crees Z, Chen W
Zebrafish. 2013 10 (2): 170-6

PMID: 23544990 · PMCID: PMC3673610 · DOI:10.1089/zeb.2012.0816

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 (CDK4(R24C)) that is insensitive to inhibition by cyclin-dependent kinase inhibitors. Our data show that expression of CDK4(R24C) in β-cells enhanced β-cell replication. CDK4(R24C) 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.

MeSH Terms (12)

Animals Animals, Genetically Modified Cell Count Cell Division Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor Proteins Fluorescent Antibody Technique Insulin Insulin-Secreting Cells Larva Zebrafish Zebrafish Proteins

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