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Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2

Abstract

Mutations in the TSC1 or TSC2 tumor suppressor genes lead to tuberous sclerosis complex (TSC), a dominant hamartomatous disorder that often presents with mental retardation, epilepsy and autism. The etiology of these neurological symptoms is unclear and the function of the TSC pathway in neurons is unknown. We found that in post-mitotic, hippocampal pyramidal neurons of mice and rats, loss of Tsc1 or Tsc2 triggered enlargement of somas and dendritic spines and altered the properties of glutamatergic synapses. Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure. Morphological changes required regulation of the actin-depolymerization factor cofilin at a conserved LIM-kinase phosphorylation site, the phosphorylation of which was increased by loss of Tsc2. Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC.

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Figure 1: Cre expression in hippocampal neurons of Tsc1C/C mice leads to loss of Tsc1 protein, increased phosphorylation of S6 and increased soma size.
Figure 2: Loss of Tsc1 leads to increased size but decreased density of dendritic spines.
Figure 3: Loss of Tsc1 increases AMPAR-mediated synaptic currents.
Figure 4: Neuronal morphology is sensitive to hemizygosity of Tsc1.
Figure 5: mTOR-dependent regulation of neuronal morphology.
Figure 6: Akt upregulation phenocopies Tsc1/Tsc2 loss but does not require phosphorylation of Tsc2 at conserved Akt phosphorylation sites.
Figure 7: Phosphorylation of cofilin is regulated by Tsc2 and is necessary for increased cell growth.

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Acknowledgements

We thank members of the Sabatini lab, D. Schmucker and D. Sabatini for comments on the manuscript; E. Hong, A. Carter and R. Witt for technical assistance and advice; and K. Mizuno, A. Minden, S. Dymecki, E. Henske, V. Ramesh, L. Cantley and Y. Shi for the gift of reagents. This work was supported by the US National Institutes of Health (5T32 NS07484) (to V.A.A.), a Burroughs Wellcome Fund Career Award, the Searle Scholars Fund, the Giovanni Armenise Foundation, the Smith Family Foundation and the US Department of Defense (TS030004).

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Correspondence to Bernardo L Sabatini.

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Supplementary information

Supplementary Fig. 1

Knock-down of Tsc2 by RNA-interference. (PDF 68 kb)

Supplementary Table 1

Summary of the analyzed data set. (PDF 53 kb)

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Tavazoie, S., Alvarez, V., Ridenour, D. et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 8, 1727–1734 (2005). https://doi.org/10.1038/nn1566

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