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Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology
Venus Thomanetz1, Nico Angliker, Dimitri Cloëtta
1Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Abstract:
The mammalian target of rapamycin (mTOR) assembles into two distinct multi-protein complexes called mTORC1 and mTORC2. Whereas mTORC1 is known to regulate cell and organismal growth, the role of mTORC2 is less understood. We describe two mouse lines that are devoid of the mTORC2 component rictor in the entire central nervous system or in Purkinje cells. In both lines neurons were smaller and their morphology and function were strongly affected. The phenotypes were accompanied by loss of activation of Akt, PKC, and SGK1 without effects on mTORC1 activity. The striking decrease in the activation and expression of several PKC isoforms, the subsequent loss of activation of GAP-43 and MARCKS, and the established role of PKCs in spinocerebellar ataxia and in shaping the actin cytoskeleton strongly suggest that the morphological deficits observed in rictor-deficient neurons are mediated by PKCs. Together our experiments show that mTORC2 has a particularly important role in the brain and that it affects size, morphology, and function of neurons.
Insights
The mammalian target of rapamycin complex 2 (mTORC2) is crucial for brain development. Deleting rictor, an mTORC2 component, in mice impaired neuron size, morphology, and function, highlighting mTORC2
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- The mammalian target of rapamycin (mTOR) pathway regulates cell growth.
- mTOR forms two complexes: mTORC1 and mTORC2.
- The specific functions of mTORC2, particularly in the central nervous system, remain less understood.
Purpose of the Study:
- To investigate the role of mTORC2 in neuronal development and function.
- To elucidate the downstream effectors of mTORC2 in the central nervous system.
Main Methods:
- Generation of mouse models lacking the mTORC2 component rictor in specific CNS regions or Purkinje cells.
- Analysis of neuronal size, morphology, and function.
- Assessment of signaling pathway activation, including Akt, PKC, and SGK1.
Main Results:
- Rictor deficiency in neurons led to smaller cell size and altered morphology.
- Impaired neuronal function was observed in rictor-deficient mice.
- Loss of Akt, PKC, and SGK1 activation occurred without affecting mTORC1 activity.
- Decreased PKC activation correlated with impaired GAP-43 and MARCKS activation, suggesting a role in morphological deficits.
Conclusions:
- mTORC2 plays a critical role in regulating neuronal size, morphology, and function in the brain.
- PKC signaling is a key mediator of mTORC2-dependent neuronal development.
- These findings underscore the importance of mTORC2 in central nervous system integrity.
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