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Molecular and Cellular Biology, December 2005, p. 10407-10418, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10407-10418.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Dosage-Dependent Effects of Akt1/Protein Kinase B{alpha} (PKB{alpha}) and Akt3/PKB{gamma} on Thymus, Skin, and Cardiovascular and Nervous System Development in Mice

Zhong-Zhou Yang,1 Oliver Tschopp,1 Nicolas Di-Poï,2 Elisabeth Bruder,3 Anne Baudry,1 Bettina Dümmler,1 Walter Wahli,2 and Brian A. Hemmings1*

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058,1 Center for Integrative Genomics, Biology Building, University of Lausanne, Lausanne CH-1015,2 Institute of Pathology, University of Basel, Schönbeinstrasse 40, Basel CH-4031, Switzerland3

Received 28 July 2005/ Returned for modification 28 August 2005/ Accepted 14 September 2005

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.

* Corresponding author. Mailing address: Friedrich Miescher Institute for Biomedical Research, P.O. Box 2543, Maulbeerstrasse 66, Basel CH-4002, Switzerland. Phone: 41-61-697-4872. Fax: 41-61-697-3976. E-mail: brian.hemmings{at}fmi.ch.

Molecular and Cellular Biology, December 2005, p. 10407-10418, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10407-10418.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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