title: Stochastic model of Tsc1 lesions in mouse brain.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment.
authors.affiliation: Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Massachusetts General Hospital, and Program in Neuroscience, Medical School, Boston, Massachusetts, United States of America.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Prabhakar
authors.forename: June
authors.initials: J
authors.lastname: Goto
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zuang
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Jillian
authors.initials: J
authors.lastname: Brockmann
authors.forename: Davide
authors.initials: D
authors.lastname: Gianni
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C045073:Cre recombinase; D019426:Integrases