title: Complex Neurological Phenotype in Mutant Mice Lacking Tsc2 in Excitatory Neurons of the Developing Forebrain(123).
abstract: Mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex (TSC), a genetic disease often associated with epilepsy, intellectual disability, and autism, and characterized by the presence of anatomical malformations in the brain as well as tumors in other organs. The TSC1 and TSC2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling. Previous animal studies demonstrated that Tsc1 or Tsc2 loss of function in the developing brain affects the intrinsic development of neural progenitor cells, neurons, or glia. However, the interplay between different cellular elements during brain development was not previously investigated. In this study, we generated a novel mutant mouse line (NEX-Tsc2) in which the Tsc2 gene is deleted specifically in postmitotic excitatory neurons of the developing forebrain. Homozygous mutant mice failed to thrive and died prematurely, whereas heterozygous mice appeared normal. Mutant mice exhibited distinct neuroanatomical abnormalities, including malpositioning of selected neuronal populations, neuronal hypertrophy, and cortical astrogliosis. Intrinsic neuronal defects correlated with increased mTORC1 signaling, whereas astrogliosis did not result from altered intrinsic signaling, since these cells were not directly affected by the gene knockout strategy. All neuronal and non-neuronal abnormalities were suppressed by continuous postnatal treatment with the mTORC1 inhibitor RAD001. The data suggest that the loss of Tsc2 and mTORC1 signaling activation in excitatory neurons not only disrupts their intrinsic development, but also disrupts the development of cortical astrocytes, likely through the mTORC1-dependent expression of abnormal signaling proteins. This work thus provides new insights into cell-autonomous and non-cell-autonomous functions of Tsc2 in brain development.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854.
authors.forename: Beth
authors.initials: B
authors.lastname: Crowell
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854 ; College of Pharmacy, Chosun University , Gwangju 501-759, South Korea.
authors.forename: Gum Hwa
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854 ; Graduate Program in Molecular Biosciences, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854.
authors.forename: Ina
authors.initials: I
authors.lastname: Nikolaeva
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854 ; Graduate Program in Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Pozzo
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854 ; Graduate Program in Molecular Biosciences, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854 ; Graduate Program in Neuroscience, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854.
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Arcangelo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism / Q000628:therapy*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D016548:Prosencephalon / Q000254:growth & development*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: TSC; astrocyte; mTOR; neuron; rapamycin; tuberous sclerosis complex