Summary
Tuberous Sclerosis Complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, caused by mutations in either TSC1 or TSC2 genes. Most patients display severe neurological manifestations, as intractable epilepsy, mental retardation and autism, which are intimately associated to peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in patients bearing mutations in TSC1 and TSC2 is highly controversial. Similar to observations in patients, mouse modelling has suggested that higher severity of phenotype is associated to mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of both genes was achieved in differentiated astrocytes. Here we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances, and spontaneous epilepsy detected in RGC-targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as STAT3-dependent and -independent developmental stage-specific defects in the differentiation potential of ex-vivo derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 gene induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development.
- Received February 18, 2013.
- Accepted May 26, 2013.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
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