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

Abstract

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.

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

We thank J. F. Spetz and P. Kopp for their assistance with ES cell culture and embryonic aggregation and R. Portmann for help with Western blot quantifications.

B.D. is supported by the Swiss Cancer League (KFS 1167-09-2001 and KFS 01002-02-2000), O.T. is supported by the Novartis Stiftung für Medizinisch-Biologische Forschung, and Z.Z.Y. is supported, in part, by a grant from Bundesamt für Bildung und Wissenschaft (BBW 98.0176). The Friedrich Miescher Institute for Biomedical Research is funded by the Novartis Research Foundation.