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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References
Gomez, M.R., Sampson, J.R. & Whittemore, V.H. (eds.) Tuberous Sclerosis Complex (Oxford Univ. Press, New York, 1999).
Ito, N. & Rubin, G.M. Gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96, 529–539 (1999).
Potter, C.J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).
Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E. & Hariharan, I.K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001).
Gao, X. & Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383–1392 (2001).
Potter, C.J., Pedraza, L.G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4, 658–665 (2002).
Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J. & Cantley, L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).
Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4, 648–657 (2002).
Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5, 559–565 (2003).
Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).
Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).
Sepp, T., Yates, J.R. & Green, A.J. Loss of heterozygosity in tuberous sclerosis hamartomas. J. Med. Genet. 33, 962–964 (1996).
Ramesh, V. Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochem. Soc. Trans. 31, 579–583 (2003).
Dijkhuizen, P.A. & Ghosh, A. BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and MAP kinase signaling pathways. J. Neurobiol. 62, 278–288 (2005).
Tang, S.J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl. Acad. Sci. USA 99, 467–472 (2002).
Hou, L. & Klann, E. Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 24, 6352–6361 (2004).
Huber, K.M., Kayser, M.S. & Bear, M.F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1257 (2000).
Uhlmann, E.J. et al. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann. Neurol. 52, 285–296 (2002).
Kohn, A.D. et al. Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J. Biol. Chem. 273, 11937–11943 (1998).
Meng, Y., Zhang, Y., Tregoubov, V., Falls, D.L. & Jia, Z. Regulation of spine morphology and synaptic function by LIMK and the actin cytoskeleton. Rev. Neurosci. 14, 233–240 (2003).
Zhou, Q., Homma, K.J. & Poo, M.M. Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44, 749–757 (2004).
Zhang, H. et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J. Clin. Invest. 112, 1223–1233 (2003).
Mashimo, J., Maniwa, R., Sugino, H. & Nose, K. Decrease in the expression of a novel TGF beta1-inducible and ras-recision gene, TSC-36, in human cancer cells. Cancer Lett. 113, 213–219 (1997).
Tuttle, R.L. et al. Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha. Nat. Med. 7, 1133–1137 (2001).
Verdu, J., Buratovich, M.A., Wilder, E.L. & Birnbaum, M.J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat. Cell Biol. 1, 500–506 (1999).
Kwon, C.H. et al. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat. Genet. 29, 404–411 (2001).
Backman, S.A. et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat. Genet. 29, 396–403 (2001).
Dong, J. & Pan, D. Tsc2 is not a critical target of Akt during normal Drosophila development. Genes Dev. 18, 2479–2484 (2004).
Sarbassov, D.D., Guertin, D.A., Ali, S.M. & Sabatini, D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
Lamb, R.F. et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol. 2, 281–287 (2000).
Govek, E.E. et al. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat. Neurosci. 7, 364–372 (2004).
Penzes, P. et al. The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis. Neuron 29, 229–242 (2001).
Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003).
Li, Y., Inoki, K., Yeung, R. & Guan, K.L. Regulation of TSC2 by 14–3-3 binding. J. Biol. Chem. 277, 44593–44596 (2002).
Hengstschlager, M., Rosner, M., Fountoulakis, M. & Lubec, G. Tuberous sclerosis genes regulate cellular 14–3-3 protein levels. Biochem. Biophys. Res. Commun. 312, 676–683 (2003).
Nufer, O. & Hauri, H.P. ER export: call 14–3-3. Curr. Biol. 13, R391–R393 (2003).
Gohla, A. & Bokoch, G.M. 14–3-3 regulates actin dynamics by stabilizing phosphorylated cofilin. Curr. Biol. 12, 1704–1710 (2002).
Benvenuto, G. et al. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 19, 6306–6316 (2000).
Sarbassov, D.D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).
Arber, S. et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 805–809 (1998).
Tassabehji, M. et al. LIM-kinase deleted in Williams syndrome. Nat. Genet. 13, 272–273 (1996).
Hayashi, M.L. et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain-specific dominant-negative PAK transgenic mice. Neuron 42, 773–787 (2004).
Bryan, B. et al. GEFT, a Rho family guanine nucleotide exchange factor, regulates neurite outgrowth and dendritic spine formation. J. Biol. Chem. 279, 45824–45832 (2004).
Meng, Y. et al. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121–133 (2002).
Chang, H. et al. Identification of a cDNA encoding a thiazide-sensitive sodium-chloride cotransporter from the human and its mRNA expression in various tissues. Biochem. Biophys. Res. Commun. 223, 324–328 (1996).
Shepherd, C.W., Houser, O.W. & Gomez, M.R. MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. AJNR Am. J. Neuroradiol. 16, 149–155 (1995).
Boyer, C., Schikorski, T. & Stevens, C.F. Comparison of hippocampal dendritic spines in culture and in brain. J. Neurosci. 18, 5294–5300 (1998).
Stoppini, L., Buchs, P.A. & Muller, D.A. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182 (1991).
Carter, A.G. & Sabatini, B.L. State dependent calcium signaling in dendritic spines of striatal medium spiny neurons. Neuron (2004).
Trachtenberg, J.T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).
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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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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DOI: https://doi.org/10.1038/nn1566
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