Dosage-Dependent Effects of Akt1/Protein Kinase Bα (PKBα) and Akt3/PKBγ on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice

Abstract

Akt/protein kinase B (PKB) plays a critical role in the regulation of metabolism, transcription, cell migration, cell cycle progression, and cell survival. The existence of viable knockout mice for each of the three isoforms suggests functional redundancy. We generated mice with combined mutant alleles of Akt1 and Akt3 to study their effects on mouse development. Here we show that Akt1^−/− Akt3^{+/ −} mice display multiple defects in the thymus, heart, and skin and die within several days after birth, while Akt1^{+/ −} Akt3^−/− mice survive normally. Double knockout (Akt1^−/− Akt3^−/−) causes embryonic lethality at around embryonic days 11 and 12, with more severe developmental defects in the cardiovascular and nervous systems. Increased apoptosis was found in the developing brain of double mutant embryos. These data indicate that the Akt1 gene is more essential than Akt3 for embryonic development and survival but that both are required for embryo development. Our results indicate isoform-specific and dosage-dependent effects of Akt on animal survival and development.

ACKNOWLEDGMENTS

We thank D. Hynx (FMI) for management of the mouse colonies and J. Günthard and T. Dieterle at the Children's Hospital and Canton Hospital, Basel, Switzerland, for consultation on Akt1^−/− Akt3^+/− heart phenotype. We are grateful to B. Sücürü and E. Fayard for antibody preparation. The Friedrich Miescher Institute for Biomedical Research is a part of the Novartis Research Foundation.

B.D. is supported by the Swiss Cancer League (KFS 1002-02-2000).