Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2.
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.
Tavazoie
Sohail F
SF
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
Alvarez
Veronica A
VA
Ridenour
Dennis A
DA
Kwiatkowski
David J
DJ
Sabatini
Bernardo L
BL
D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D048430:Cell Shape / Q000235:genetics; D051338:Cofilin 1 / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D051338:Cofilin 1; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins