Newswise — At first, it seemed a far-fetched explanation for a deadly human disease. Polycystic kidney disease (PKD) is a common genetic disorder that affects more than 600,000 Americans and 12.5 million people worldwide. Half of those diagnosed with PKD will progress to end-stage renal disease by the age of 60. PKD is characterized by the inappropriate formation of multiple epithelial cell-lined cavities in the kidney, but what triggers overgrowth in these cells was a mystery until recently when cell biologists made a radical suggestion: Could PKD be caused by defective cilia?
Cilia are small hair-like structures that protrude from the surface of a wide range of cells, much like antennae. Cilia are ancient and useful biological structures. Waving cilia propel one-celled organisms like paramecia. Waving cilia in human bronchial linings keep airways clear. Cilia in human kidneys, it was thought, didn't do much of anything. Kidney cilia were considered leftover evolutionary baggage like the vestigial appendix or wisdom teeth. So the first evidence that genes encoding defective kidney cilia were somehow related to PKD was met by skepticism. How could something that doesn't appear to do anything be the cause of something as catastrophic as PKD?
The cilia, it turns out, are it. A new study by Zhaoxia Sun of the Yale University School of Medicine and her colleagues at MIT and the University of Massachusetts Medical School provides yet more compelling evidence that defective cilia are the predominant cause of cystic kidney disease. Moreover, these findings led Sun to offer a possible explanation of how defective cilia cause kidney epithelial cell overgrowth; the cilia act as biomechanical sensors.
As a postdoctoral fellow with Nancy Hopkins at MIT, Sun chose the small tropical zebrafish as a model organism to study kidney disease. Using an insertational mutagenesis screen, she identified 12 different fish genes that cause cysts in the glomerular-tubular kidney region when mutated. Two of these, vHNF1 and PKD2, were already associated with human cystic kidney disease. Later, Sun made the critical discovery that at least five of the newly-isolated fish genes are functionally linked to cilia.
Remarkably, the mutated genes not only produced PDK-like cysts in zebrafish, they also increased the diameter of the kidney tubes, whereas normal kidney tubes almost always remain constant in size. This result led Sun and her colleagues to their new PKD model. "The cilia on kidney epithelial cells function as sensors for the size of the tubes," Sun explains. "Signals from the cilia tell the cells to stop growing when the tubes reach a certain size. Once this brake is lost, the kidney epithelial cells will keep on proliferating and kidney cysts will form as a result." Meantime, Sun says that the 10 additional genes identified in her zebrafish screen are all good candidates as analogs for as yet undiscovered human PKD-related genes.
A Genetic Screen in Zebrafish Identifies Cilia Genes as a Principal Cause of Cystic Kidney and Links the Cilium to Size Control of Epithelial Tubes, Z. Sun,1 A. Amsterdam,2 G. J. Pazour,3 N. Hopkins2 ; 1 Genetics, Yale University School of Medicine, New Haven, CT, 2 Center for Cancer Research, MIT, Boston, MA, 3 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
At the meeting: Session 474, Minisymposium 29: Intraflagellar Transport in Human Health, Room 147. Author presents: 3:15—5:20 PM.
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