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Molecular and Cellular Biology, March 2005, p. 1869-1878, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1869-1878.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role for Akt3/Protein Kinase B{gamma} in Attainment of Normal Brain Size

Rachael M. Easton,1 Han Cho,1,2 Kristin Roovers,1 Diana W. Shineman,3 Moshe Mizrahi,4 Mark S. Forman,3 Virginia M.-Y. Lee,3 Matthias Szabolcs,5 Ron de Jong,6,7 Tilman Oltersdorf,6 Thomas Ludwig,8,9 Argiris Efstratiadis,9,10 and Morris J. Birnbaum1,4*

Department of Medicine, Center for Neurodegenerative Disease Research,1 Department of Pathology and Laboratory Medicine and Institute on Aging,3 Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,4 Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire,2 Departments of Pathology,5 Anatomy and Cell Biology,8 Genetics and Development,10 Institute for Cancer Genetics, Columbia University, New York, New York,9 IDUN Pharmaceuticals, Inc.,6 Syrrx, Inc., San Diego, California7

Received 23 September 2004/ Returned for modification 6 November 2004/ Accepted 5 December 2004

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1–/– mice, which display a proportional decrease in the sizes of all organs, Akt3–/– mice present a selective 20% decrease in brain size. Moreover, although Akt1- and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3–/– but not Akt1–/– mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.

* Corresponding author. Mailing address: University of Pennsylvania School of Medicine, Clinical Research Building 322, 415 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 898-5001. Fax: (215) 573-9138. E-mail: birnbaum{at}mail.med.upenn.edu.

Molecular and Cellular Biology, March 2005, p. 1869-1878, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1869-1878.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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