Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2.

By Xiao-ding Peng, Pei-Zhang Xu, Mei-Ling Chen, Annett Hahn-Windgassen, Jennifer E. Skeen, J. Jacobs, Deepa Sundararajan, William S. Chen, S. Crawford, K. Coleman and 1 more. Genes & Development, 2003

881 citations recorded by the source corpus.

To elucidate the functions of the serine/threonine kinase Akt/PKB in vivo, we generated mice lacking both akt1 and akt2 genes. Akt1/Akt2 double-knockout (DKO) mice exhibit severe growth deficiency and die shortly after birth. These mice display impaired skin development because of a proliferation defect, severe skeletal muscle atrophy because of a marked decrease in individual muscle cell size, and impaired bone development. These defects are strikingly similar to the phenotypes of IGF-1 receptor-deficient mice and suggest that Akt may serve as the most critical downstream effector of the IGF-1 receptor during development. In addition, Akt1/Akt2 DKO mice display impeded adipogenesis. Specifically, Akt1 and Akt2 are required for the induced expression of PPARgamma, the master regulator of adipogenesis, establishing a new essential role for Akt in adipocyte differentiation. Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation. These functions of Akt were uncovered despite the observed lower level of Akt activity mediated by Akt3 in Akt1/Akt2 DKO cells, suggesting that a critical threshold level of Akt activity is required to maintain normal cell proliferation, growth, and differentiation.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0e5149ab963fd9d32437b8844f68ee2ead458d90

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In Genetics

1. David M. Sabatini
2. Nahum Sonenberg
3. T. Mak
4. T. Franke

In Molecular Biology

1. David M. Sabatini
2. T. Franke
3. Nahum Sonenberg
4. C. Thoreen
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6. D. Guertin
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Citations in the corpus

• Deregulated Akt3 Activity Promotes Development of Malignant Melanoma (2004, background): “In contrast, Akt2 knockout mice have impaired insulin regulation and consequently a defective capability of lowering blood glucose levels due to defects in the action of insulin on liver and skeletal muscle (16, 18).”
• Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size (2005, result): “Some indication that this is the case is provided by the observation that in Akt1 / Akt2 / mice, skeletal muscle atrophy is due to decreased myocyte size, whereas there is a reduced number of cells in the skin (58).”
• Mitochondrial complex III ROS regulate adipocyte differentiation (2011, neutral): “Akt activation downstream of insulin signaling makes multiple contributions to adipocyte differentiation and is required for the process (Peng et al., 2003).”
• Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. (2005, neutral): “However, these genes display a considerable degree of functional overlap, as combined deletion of Akt1 and Akt2 genes results in perinatal lethality with severe growth retardation and multiple developmental defects (18).”
• Cellular and molecular mechanisms of muscle atrophy (2013, neutral): “…factors, which play major roles as mediators of immunity and inflammation, are also expressed in skeletal muscle, where they mediate the effect of inflammatory cytokines, particularly tumor necrosis factor-α (TNFα), on muscle wasting and cachexia (reviewed in Peterson et al., 2011) (Fig.”
• Upstream and downstream of mTOR. (2004, background): “Studies with mice lacking two (Akt1 and Akt2) of the three Akt proteins provide the first genetic evidence that Akt functions upstream of mTOR in mammalian cells (Peng et al. 2003).”
• Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery (2005, background): “In knockout mice, elimination of different isoforms leads to different developmental defects and alterations in insulin sensitivit”
• S6K1−/−/S6K2−/− Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5′-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase Pathway (2004, background): “It should also be noted that the combined inactivation of two other elements of the phosphatidylinositide-3OH kinase pathway, Akt1 and Akt2, also leads to perinatal lethality of unknown cause (43).”
• Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. (2004, background): “Akt1/Akt2 doubly deficient mice also show impeded adipogenesis due to impaired induction of PPARγ (31).”
• SREBP Activity Is Regulated by mTORC1 and Contributes to Akt-Dependent Cell Growth (2008, background): “Akt1/Akt2 double-knockout mice exhibit severe growth deficiency (Peng et al., 2003) and mice deficient in S6-kinase 1 (S6K1) show a significant reduction in size accompanied by hypoinsulinaemia and glucose intolerance (Pende et al.”