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Fatty acids increase neuronal hypertrophy of Pten knockdown neurons
Catherine J Fricano1, Tyrone Despenza1, Paul W Frazel1
1Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA.
Abstract:
Phosphatase and tensin homolog (Pten) catalyzes the reverse reaction of PI3K by dephosphorylating PIP3 to PIP2. This negatively regulates downstream Akt/mTOR/S6 signaling resulting in decreased cellular growth and proliferation. Co-injection of a lentivirus knocking Pten down with a control lentivirus allows us to compare the effects of Pten knockdown between individual neurons within the same animal. We find that knockdown of Pten results in neuronal hypertrophy by 21 days post-injection. This neuronal hypertrophy is correlated with increased p-S6 and p-mTOR in individual neurons. We used this system to test whether an environmental factor that has been implicated in cellular hypertrophy could influence the severity of the Pten knockdown-induced hypertrophy. Implantation of mini-osmotic pumps delivering fatty acids results in increased neuronal hypertrophy and p-S6/p-mTOR staining. These hypertrophic effects were reversed in response to rapamycin treatment. However, we did not observe a similar increase in hypertrophy in response to dietary manipulations of fatty acids. Thus, we conclude that by driving growth signaling with fatty acids and knocking down a critical regulator of growth, Pten, we are able to observe an additive morphological phenotype of increased soma size mediated by the mTOR pathway.
Insights
Knocking down Pten in neurons caused them to grow larger, an effect amplified by fatty acids. This neuronal hypertrophy, mediated by mTOR signaling, was reversed by rapamycin.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Phosphatase and tensin homolog (Pten) is a key negative regulator of the PI3K/Akt pathway.
- Pten dephosphorylates PIP3 to PIP2, inhibiting downstream Akt/mTOR/S6 signaling and thus cellular growth.
- Dysregulation of Pten is implicated in various cellular hypertrophy conditions.
Purpose of the Study:
- To investigate the role of Pten in neuronal hypertrophy.
- To determine if environmental fatty acid exposure exacerbates Pten knockdown-induced neuronal hypertrophy.
- To elucidate the molecular mechanisms underlying Pten-mediated neuronal growth.
Main Methods:
- Utilized lentiviral vectors for Pten knockdown in individual neurons within the same animal for comparative analysis.
- Assessed neuronal hypertrophy and quantified levels of phosphorylated S6 (p-S6) and phosphorylated mTOR (p-mTOR) via staining.
- Administered fatty acids via mini-osmotic pumps and tested the effects of rapamycin treatment and dietary fatty acid manipulation.
Main Results:
- Pten knockdown led to significant neuronal hypertrophy by 21 days post-injection.
- Hypertrophy was correlated with increased p-S6 and p-mTOR levels.
- Fatty acid administration via pumps exacerbated hypertrophy and mTOR pathway activation, an effect reversed by rapamycin, while dietary changes had no effect.
Conclusions:
- Pten knockdown induces neuronal hypertrophy mediated by the mTOR pathway.
- Environmental fatty acid delivery can enhance Pten knockdown-induced hypertrophy.
- The mTOR pathway is a critical mediator of Pten-regulated neuronal growth and soma size.
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