Zinc Finger Protein Zbtb20 Is Essential for Postnatal Survival and Glucose Homeostasis

Abstract

Zbtb20 is a member of the POK family of proteins, which function primarily as transcriptional repressors via interactions mediated by their conserved C₂H₂ Krüppel type zinc finger and BTB/POZ domains. To define the function of Zbtb20 in vivo, we generated knockout mice by homologous recombination. Zbtb20 null mice display a stark phenotype characterized by postnatal growth retardation, metabolic dysfunction, and lethality. Zbtb20 knockout mice displayed abnormal glucose homeostasis, hormonal responses, and depletion of energy stores, consistent with an energetic deficit. Additionally, increased serum bilirubin and alanine aminotransferase levels were suggestive of liver dysfunction. To identify potential liver-specific Zbtb20 target genes, we performed transcript profiling studies on liver tissue from Zbtb20 knockout mice and wild-type littermate controls. These studies identified sets of genes involved in growth, metabolism, and detoxification that were differentially regulated in Zbtb20 knockout liver. Transgenic mice expressing Zbtb20 in the liver were generated and crossed onto the Zbtb20 knockout background, which resulted in no significant normalization of growth or glucose metabolism but a significant increase in life span compared to controls. These data indicate that the phenotype of Zbtb20 knockout mice results from liver-dependent and -independent defects, suggesting that Zbtb20 plays nonredundant roles in multiple organ systems.

ACKNOWLEDGMENTS

We thank Kirsten Sigrist, Jennifer Donovan, Diana Pascual, and the staff at the Harvard School of Public Health Animal Testing Facility for assistance with animal care.

This work was supported by gift from the G. Harold and Leila Y. Mathers Charitable Foundation (to M.J.G.) and National 973 Program of China, grant 2006CB503910 (to W.J.Z.). A. P. R. Sutherland is a CJ Martin Fellow of the NH&MRC of Australia.

We have no conflicting financial interests.