Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila.

Chiara Gamberi,William D. Lubell,Marie Trudel,David R. Hipfner,Claude Desplan

doi:10.1371/journal.pgen.1006694

Abstract

Progressive cystic kidney degeneration underlies diverse renal diseases, including the most common cause of kidney failure, autosomal dominant Polycystic Kidney Disease (PKD). Genetic analyses of patients and animal models have identified several key drivers of this disease. The precise molecular and cellular changes underlying cystogenesis remain, however, elusive. Drosophila mutants lacking the translational regulator Bicaudal C (BicC, the fly ortholog of vertebrate BICC1 implicated in renal cystogenesis) exhibited progressive cystic degeneration of the renal tubules (so called “Malpighian” tubules) and reduced renal function. The BicC protein was shown to bind to Drosophila (d-) myc mRNA in tubules. Elevation of d-Myc protein levels was a cause of tubular degeneration in BicC mutants. Activation of the Target of Rapamycin (TOR) kinase pathway, another common feature of PKD, was found in BicC mutant flies. Rapamycin administration substantially reduced the cystic phenotype in flies. We present new mechanistic insight on BicC function and propose that Drosophila may serve as a genetically tractable model for dissecting the evolutionarily-conserved molecular mechanisms of renal cystogenesis.

Highlights

Maintenance of structural and functional integrity of the kidney is a complex, crucial task presided over by the activity of numerous genes
Polycystic Kidney Disease (PKD) causes the formation of prominent, fluid-filled cysts the growth of which damages progressively kidney function
Crucial to PKD development, mutations in the PKD1 and PKD2 genes cause renal cystic degeneration via factors and mechanisms that are only partially known. This manuscript reports novel insights into the molecular mechanisms of the evolutionarily conserved RNA binding protein Bicaudal C (BicC), which has been implicated in vertebrate cystic kidney diseases

Summary

Introduction

Maintenance of structural and functional integrity of the kidney is a complex, crucial task presided over by the activity of numerous genes. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common cause of end-stage renal failure, affects 12.5 million people world-wide and has an incidence of 1–2 cases per 2000 live births world-wide [1]. Mutations in the PKD1 and PKD2 genes account for the majority of the genetic lesions in ADPKD patients [3,4]. Activation of the mammalian (m) TOR pathway was found in various forms of renal cystic pathologies, including human ADPKD cysts, autosomal recessive PKD, and rodent models of PKD and nephronophthisis [5,6,7,9,10,11]. Genetic analyses have indicated that some signaling pathways are altered in PKD tissue, the precise molecular and cellular changes underlying cystogenesis in PKD and other diseases remain elusive

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