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

Abstract:

: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.

journal_name

Zebrafish

journal_title

Zebrafish

authors

Li M,Maddison LA,Crees Z,Chen W

doi

10.1089/zeb.2012.0816

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

170-6

issue

2

eissn

1545-8547

issn

1557-8542

journal_volume

10

pub_type

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