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Molecular and Cellular Biology, November 2006, p. 8042-8051, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00722-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Life with a Single Isoform of Akt: Mice Lacking Akt2 and Akt3 Are Viable but Display Impaired Glucose Homeostasis and Growth Deficiencies{triangledown} ,{dagger}

Bettina Dummler,1 Oliver Tschopp,1 Debby Hynx,1 Zhong-Zhou Yang,1 Stephan Dirnhofer,2 and Brian A. Hemmings1*

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland,1 Institute of Pathology, University of Basel, Schönbeinstrasse 40, Basel CH-4031, Switzerland2

Received 26 April 2006/ Returned for modification 1 June 2006/ Accepted 13 August 2006

To address the issues of isoform redundancy and isoform specificity of the Akt family of protein kinases in vivo, we generated mice deficient in both Akt2 and Akt3. In these mice, only the Akt1 isoform remains to perform essential Akt functions, such as glucose homeostasis, proliferation, differentiation, and early development. Surprisingly, we found that Akt2–/– Akt3–/– and even Akt1+/– Akt2–/– Akt3–/– mice developed normally and survived with minimal dysfunctions, despite a dramatic reduction of total Akt levels in all tissues. A single functional allele of Akt1 appears to be sufficient for successful embryonic development and postnatal survival. This is in sharp contrast to the previously described lethal phenotypes of Akt1–/– Akt2–/– mice and Akt1–/– Akt3–/– mice. However, Akt2–/– Akt3–/– mice were glucose and insulin intolerant and exhibited an ~25% reduction in body weight compared to wild-type mice. In addition, we found substantial reductions in relative size and weight of the brain and testis in Akt2–/– Akt3–/– mice, demonstrating an in vivo role for both Akt2 and Akt3 in the determination of whole animal size and individual organ sizes.

* Corresponding author. Mailing address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland. Phone: 41 61 697 4872. Fax: 41 61 697 3976. E-mail: brian.hemmings{at}fmi.ch.

{triangledown} Published ahead of print on 21 August 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 8042-8051, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.00722-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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