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Published on: April 1, 2022
Constitutively active Akt induces ectodermal defects and impaired bone morphogenetic protein signaling
Carmen Segrelles1, Marta Moral, Corina Lorz
1Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, E-28040 Madrid, Spain.
Abstract:
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.
Insights
Deregulated Akt signaling disrupts epithelial development and homeostasis. Constitutively active Akt1 in mice impairs ectodermal organ formation and alters stem cell function, highlighting Akt
Area of Science:
- Molecular Biology
- Developmental Biology
- Dermatology
Background:
- Aberrant Akt pathway activation is linked to human pathologies like cancer.
- Limited understanding exists regarding Akt signaling's role in biological development.
- Akt signaling may be crucial for epidermal homeostasis via cell-autonomous and non-cell-autonomous mechanisms.
Purpose of the Study:
- To investigate the developmental effects of deregulated Akt activity in stratified epithelia.
- To explore the molecular mechanisms underlying these developmental alterations.
Main Methods:
- Utilized transgenic mice expressing constitutively active Akt1 (myrAkt) and wild-type Akt1 (Akt(wt)).
- Conducted gene profiling to identify molecular pathways affected by constitutive Akt activity.
- Observed dose-dependent effects on ectodermally derived organs and adult epidermal stem cells.
Main Results:
- myrAkt mice exhibited dose-dependent alterations in hair, teeth, nails, and epidermal glands development.
- Constitutive Akt activity was found to disrupt the bone morphogenetic protein signaling pathway.
- Significant alterations were observed in adult epidermal stem cells of myrAkt mice.
Conclusions:
- Proper regulation of Akt expression and activity is essential for epithelial tissue development.
- Deregulated Akt signaling profoundly impacts epidermal homeostasis and organogenesis.
- Akt pathway dysregulation affects key developmental signaling, including BMP.
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