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.
Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
June
J
Goto
Delia M
DM
Talos
Peter
P
Klein
Wei
W
Qin
Yvonne I
YI
Chekaluk
Stefanie
S
Anderl
Izabela A
IA
Malinowska
Alessia
A
Di Nardo
Roderick T
RT
Bronson
Jennifer A
JA
Chan
Harry V
HV
Vinters
Steven G
SG
Kernie
Frances E
FE
Jensen
Mustafa
M
Sahin
David J
DJ
Kwiatkowski
D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D020123:Sirolimus