Bicaudal C mutation reveals core conserved mechanisms of renal cyst formation

Cassandra Millet-Boureima¹, Susannah Selber-Hnatiw¹, Helene Ben Soussan¹, Joshua Oliver¹, Jessica Porras-Marroquin¹, Kahlila Paul-Cole¹, Debra Fulton², Ethan Yang³, Ramesh Chingle³,Roman Rozencwaig⁴,Samuel Tayar⁴, Felix Polyak⁴,Pierre Chaurand³, William D. Lubell³, David Hipfner⁵ and Chiara Gamberi¹

¹ Department of Biology, Concordia University, Montreal, Canada; ²Genomics Institute, Concordia University, Montreal, Canada; ³Chemistry Department, Université de Montréal, Montreal, Canada;⁴BH Bioscience Inc.,Montreal, Canada;⁵Institut de recherches cliniques de Montréal, Montreal, Canada

Progressive cystic kidney degeneration underlies autosomal dominant Polycystic Kidney Disease (PKD). Incurable, ADPKD affects 66,000 Canadians and 12.5 million people world-wide; its molecular and cellular mechanisms remain unknown.¹ The vertebrate kidney is known to be relatively genetically intractable, however, the fly’s Malpighian (renal) tubule displays remarkable conservation and has been used to model renal tubule function.²

In my laboratory, we found that Drosophila mutants of the gene Bicaudal C³ (BicC, the ortholog of vertebrate BICC1 implicated in renal cystogenesis) recapitulated crucial features of PKD, including progressive cystic degeneration of the Malpighian tubules, defective renal function, myc and TOR up-regulation.⁴ Indicating conserved BicC implication into core cystic pathways, BicCloss-of-function was observed in cysts from PKD patients carrying mutations in PKD1 (linked to ADPKD), and kidneys of the murine Pkd1^-/- model of ADPKD.⁴ BicC is an RNA-binding protein discovered in the fly ovary.³ We found that in Malpighian tubules, the BicC protein binds to Drosophila myc mRNA and BicC mutants displayedaccumulation of the cognate Myc protein which contributed to tubular degeneration.⁴ Alike PKD patients, rapamycin administration to BicC mutant flies reduced the cystic phenotype.⁴ A combination of genetic, molecular, transcriptomic and mass spectrometry studies is being utilized to define the molecular defects underpinning cyst formation in the renal tubule and its progressive degeneration. Complementary chemical probing for the BicC-dependent pathways in adult flies has yielded several molecules capable of rescuing the cystic degeneration of the BicC Malpighian tubule, which will aid the rational development of novel PKD therapies.

Selected references

1 Harris, P. C. & Torres, V. E. Polycystic kidney disease. Annu Rev Med 60, 321-337, doi:10.1146/annurev.med.60.101707.125712 (2009).

2 Millet-Boureima, C., Porras Marroquin, J. & Gamberi, C. Modeling Renal Disease "On the Fly". Biomed Res Int 2018, 5697436, doi:10.1155/2018/5697436 (2018).

3 Gamberi, C. (corr.) & Lasko, P. The Bic-C family of developmental translational regulators. Comp Funct Genomics 2012, 141386, doi:10.1155/2012/141386 (2012).

4 Gamberi, C. (corr.), Hipfner, D. R., Trudel, M., Lubell, W. D. Bicaudal C mutation causes myc and TOR pathway up-regulation and polycystic kidney disease-like phenotypes in Drosophila. PLoS Genet 13, e1006694, doi:10.1371/journal.pgen.1006694 (2017).

5 Millet-Boureima C.*, Selber-Hnatiw S.*, and Gamberi C. “Drugging flies for drug discovery and chemical probing”. Genome, special issue on Canadian Fly Research. 2020. In press. https://doi.org/10.1139/gen-2020-0037