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Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of Tsc1 loss in neural progenitor cells in Tsc1(cc) Nestin-rtTA(+) TetOp-cre(+) embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly, Tsc1-null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of Tsc1 loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.

Pubmed ID: 22025691

Authors

  • Goto J
  • Talos DM
  • Klein P
  • Qin W
  • Chekaluk YI
  • Anderl S
  • Malinowska IA
  • Di Nardo A
  • Bronson RT
  • Chan JA
  • Vinters HV
  • Kernie SG
  • Jensen FE
  • Sahin M
  • Kwiatkowski DJ

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 8, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: 1P01NS24279
  • Agency: NICHD NIH HHS, Id: P30-HD-18655
  • Agency: NINDS NIH HHS, Id: R01 NS58956

Mesh Terms

  • Animals
  • Blotting, Western
  • Cell Survival
  • Disease Models, Animal
  • Humans
  • Mice
  • Microscopy, Electron
  • Microscopy, Fluorescence
  • Neurons
  • Polymerase Chain Reaction
  • Sirolimus
  • Stem Cells
  • Tuberous Sclerosis
  • Tumor Suppressor Proteins