Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 21, Issue 4, Pages 561-574Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/mcne.2002.1184
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- NIMH NIH HHS [MH01658] Funding Source: Medline
- NINDS NIH HHS [NS39938, NS31535, NS41498] Funding Source: Medline
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Cortical tubers are developmental brain malformations in the tuberous sclerosis complex (TSC) that cause epilepsy and autism in TSC patients whose pathogenesis is uncertain. Tsc2 null murine neuroepithelial progenitor (NEP) cells display persistent growth when growth factors are withdrawn, express GFAP at high levels, and have reduced expression of a set of early neuronal lineage markers. Tsc2 null NEP cells exhibit aberrant differentiation into giant cells that express both betaIII-tubulin and GFAP and that are morphologically similar to giant cells in human tubers. Tsc2 null giant cells and tuber giant cells have similar transcriptional profiles. Tsc2 null NEP cells express high levels of phosphorylated S6kinase, S6, Stat3, and 4E-BP-1, which is reversed by treatment with rapamycin, an inhibitor of mTOR. We conclude that giant cells in human tubers likely result from a complete loss of TSC2 expression and activation of an mTOR pathway during cortical development.
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