Human Molecular Genetics Advance Access originally published online on March 25, 2009
Human Molecular Genetics 2009 18(12):2166-2176; doi:10.1093/hmg/ddp149
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Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis
1 Institute of Medical Genetics 2 Medical Microscopy Sciences, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK 3 Department of Medical Genetics, University of Cambridge, Cambridge CB2 0XY, UK
* To whom correspondence should be addressed. Tel: +44 2920742652; Fax: +44 2920746551; Email: cheadlejp{at}cardiff.ac.uk
Received February 26, 2009; Revised February 26, 2009; Accepted March 23, 2009
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.