Nature Neuroscience 8, 1727 - 1734 (2005)
Published online: 6 November 2005; | doi:10.1038/nn1566
Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2Sohail F Tavazoie1, 3, 4, Veronica A Alvarez1, 4, Dennis A Ridenour1, David J Kwiatkowski2
& Bernardo L Sabatini11
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. 2
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115, USA. 3
Present address: Department of Medical Oncology/Hematology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Bernardo L Sabatini bsabatini@hms.harvard.edu 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
