The first two authors contributed equally.
Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants
Article first published online: 25 SEP 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Comparative Neurology
Volume 521, Issue 16, pages 3817–3831, November 2013
How to Cite
Mietzsch, U., McKenna, J., Reith, R. M., Way, S. W. and Gambello, M. J. (2013), Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants. J. Comp. Neurol., 521: 3817–3831. doi: 10.1002/cne.23380
- Issue published online: 25 SEP 2013
- Article first published online: 25 SEP 2013
- Accepted manuscript online: 8 JUN 2013 01:31AM EST
- Manuscript Accepted: 24 MAY 2013
- Manuscript Revised: 27 FEB 2013
- Manuscript Received: 29 AUG 2012
- National Institutes of Health (NIH) . Grant Number: R01NS060804 (to M.J.G.)
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with variable expressivity. Heterozygous mutations in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for most cases. Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) kinase. Genotype-phenotype studies suggest that TSC2 mutations are associated with a more severe neurologic phenotype, although the biologic basis for the difference between TSC1- and TSC2-based disease is unclear. Here we performed a study to compare and contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants. Using Tsc1 and Tsc2 floxed alleles and a radial glial transgenic Cre driver (FVB-Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells. Single and double mutants had remarkably similar phenotypes: early postnatal mortality, brain overgrowth, laminar disruption, astrogliosis, a paucity of oligodendroglia, and myelination defects. Double Tsc1/Tsc2 mutants died earlier than single mutants, and single mutants showed differences in the location of heterotopias and the organization of the hippocampal stratum pyramidale. The differences were not due to differential mTORC1 activation or feedback inhibition on Akt. These data provide further genetic evidence for individual hamartin and tuberin functions that may explain some of the genotype–phenotype differences seen in the human disease. J. Comp. Neurol. 521:3817–3831, 2013. © 2013 Wiley Periodicals, Inc.