Role for Akt3/protein kinase Bgamma in attainment of normal brain size.
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.
Easton
Rachael M
RM
Department of Medicine, University of Pennsylvania School of Medicine, Clinical Research Building 322, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Cho
Han
H
Roovers
Kristin
K
Shineman
Diana W
DW
Mizrahi
Moshe
M
Forman
Mark S
MS
Lee
Virginia M-Y
VM
Szabolcs
Matthias
M
de Jong
Ron
R
Oltersdorf
Tilman
T
Ludwig
Thomas
T
Efstratiadis
Argiris
A
Birnbaum
Morris J
MJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C494922:Akt2 protein, mouse; C491753:Akt3 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D005947:Glucose