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Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using 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 showed a genetic interaction between  Tsc1  and  Tsc2  with  Pkd1  and confirmed an mTOR-independent pathway of renal cystogenesis. We observed that the  Tsc  and  Pkd1  gene products helped regulate primary cilia length and, consistent with the function of this organelle in modulating cell polarity, found that many dividing pre-cystic renal tubule and hepatic bile duct cells from  Tsc1 ,  Tsc2  and  Pkd1  heterozygous mice were highly misoriented. We therefore propose that defects in cell polarity underlie TSC and ADPKD-associated cystic disease and targeting of this pathway may be of key therapeutic benefit.

Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis