Constitutively active Akt induces ectodermal defects and impaired bone morphogenetic protein signaling.
Aberrant activation of the Akt pathway has been implicated in several human pathologies including cancer. However, current knowledge on the involvement of Akt signaling in development is limited. Previous data have suggested that Akt-mediated signaling may be an essential mediator of epidermal homeostasis through cell autonomous and noncell autonomous mechanisms. Here we report the developmental consequences of deregulated Akt activity in the basal layer of stratified epithelia, mediated by the expression of a constitutively active Akt1 (myrAkt) in transgenic mice. Contrary to mice overexpressing wild-type Akt1 (Akt(wt)), these myrAkt mice display, in a dose-dependent manner, altered development of ectodermally derived organs such as hair, teeth, nails, and epidermal glands. To identify the possible molecular mechanisms underlying these alterations, gene profiling approaches were used. We demonstrate that constitutive Akt activity disturbs the bone morphogenetic protein-dependent signaling pathway. In addition, these mice also display alterations in adult epidermal stem cells. Collectively, we show that epithelial tissue development and homeostasis is dependent on proper regulation of Akt expression and activity.
Segrelles
Carmen
C
Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, E-28040 Madrid, Spain.
Moral
Marta
M
Lorz
Corina
C
Santos
Mirentxu
M
Lu
Jerry
J
Cascallana
José Luis
JL
Lara
M Fernanda
MF
Carbajal
Steve
S
Martínez-Cruz
Ana Belén
AB
García-Escudero
Ramón
R
Beltran
Linda
L
Segovia
José C
JC
Bravo
Ana
A
DiGiovanni
John
J
Paramio
Jesús M
JM
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004475:Ectoderm / Q000002:abnormalities* / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D004817:Epidermis / Q000201:enzymology / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006197:Hair / Q000002:abnormalities / Q000648:ultrastructure; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009264:Nails, Malformed / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D014071:Tooth Abnormalities / Q000201:enzymology
D019485:Bone Morphogenetic Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt