Genetics and cell biology

Molecular basis of cystic kidney disorders


Group leader

Alessandra Boletta


The unit is interested in understanding the morphogenetic mechanisms driving establishment and maintenance of renal tubular diameter in physiological conditions and that are deranged in pathologies such as cystic kidney disorders. This group uses as a prototype disease Polycystic Kidney Disease (PKD), a genetic disorder, due to mutations in two genes: PKD1 and PKD2, encoding for two membrane proteins Polycystin-1 and 2, respectively. The two proteins localize in cilia, their precise function is unclear.

Over the years this unit found that Polycystin-1 and 2 regulate the cellular cytoskeleton and cell migration as well as tissue morphogenesis in the developing kidney. Furthermore, they discovered that metabolic reprogramming is a key feature of PKD which includes the use of aerobic glycolysis, glutaminolysis and mitochondrial impairment. Several of these derangements depend on the mTOR pathway.

Research activity

Key questions that we are trying to address are:
  • What is the normal function of the Polycystins? And their role in epithelial morphogenesis during renal development?
  • Is the function of the polycystins exclusively due to their activity in cilia, or there are additional functional roles for these proteins?
  • What is the origin of the metabolic derangement and mitochondrial alterations observed in PKD animal models?
  • Why despite the numerous similarities with cancer, PKD cysts do not transform into carcinomas?
In recent years the unit has generated mice lacking the Tsc1 gene in the kidney. They undergo slowly progressive cyst formation caused by downregulation of Polycystin-1. Of interest, the cysts progressively transform into cystadenomas and carcinomas. This group is focusing on studying the metabolic alterations downstream of the mTORC1 pathway that drive the transformation of renal epithelia into cystadenomas and carcinomas.