| Popis: |
Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by germline mutations in either TSC1 or TSC2 and characterised by the development of benign hamartomatous growths in multiple organs and tissues. Clinical trials are underway for the treatment of TSC-associated tumours using mammalian target of rapamycin (mTOR) inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/ and Tsc2+/ mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co- deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys. Using mouse models, we crossed Tsc1+, and Tsc2+I mice with Pkd1+/ mice to generate double heterozygotes. We found that Tsc1+lPkd1+, and Tsc2+l Pkd1+, mice had significantly more renal lesions than their corresponding single heterozygote littermates indicating a genetic interaction between Tsd and Tsc2 with Pkd1. In agreement with our findings from Tsc1+/ and Tsc2+/ mice, we found that a large proportion of cysts from Tsc1+l Pkd1+, and Tsc2+l Pkd1+, mice failed to stain for pS6, suggesting that initiation of renal cystogenesis in these animals may occur independently of mTOR activation. We analysed primary cilia in phenotypically normal renal tubule epithelial cells by scanning electron microscopy (SEM) and found that those from Tsc1+, and Tsc2+I mice were significantly shorter than those from wild-type littermates (2.122pm and 2.016pm vs. 2.233pm, respectively, P |
