Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation.
Individuals with tuberous sclerosis complex (TSC) develop central nervous system abnormalities that may reflect astrocyte dysfunction. In an effort to model astrocyte dysfunction in TSC, we generated mice lacking Tsc1 (hamartin) expression in astrocytes and demonstrated that Tsc1-null astrocytes exhibit abnormalities in contact inhibition growth arrest. In this study, we demonstrate that hamartin-deficient astrocytes are also defective in cell size regulation. We show that the increase in Tsc1-null astrocyte size is associated with increased activation of the S6-kinase pathway. In keeping with recent reports that the hamartin/tuberin complex may regulate Rheb and downstream S6K activation, we demonstrate that expression of either Rheb or S6K in primary astrocytes results in increased S6 pathway activation, and that inhibition of Rheb activity in Tsc1-deficient astrocytes using either pharmacologic or genetic strategies markedly reduces S6 activation. Collectively, these observations suggest that TSC inactivation in astrocytes results in defective cell size regulation associated with dysregulated Rheb/mTOR/S6K pathway activity.
Uhlmann
Erik J
EJ
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Li
Wen
W
Scheidenhelm
Danielle K
DK
Gau
Chia-Ling
CL
Tamanoi
Fuyuhiko
F
Gutmann
David H
DH
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D003260:Contact Inhibition / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014162:Transfection; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000235:genetics
D004791:Enzyme Inhibitors; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D020559:Monomeric GTP-Binding Proteins