Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies.
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 approximately 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.
Dummler
Bettina
B
Friedrich Miescher Institute for Biomedical Research, Basel CH-4058, Switzerland.
Tschopp
Oliver
O
Hynx
Debby
D
Yang
Zhong-Zhou
ZZ
Dirnhofer
Stephan
S
Hemmings
Brian A
BA
D000818:Animals; D001835:Body Weight; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009929:Organ Size; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013737:Testis / Q000033:anatomy & histology / Q000378:metabolism
D007328:Insulin; D020033:Protein Isoforms; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose