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.