Within our kidneys, the dense winding ductwork that carries urine to the bladder is lined with cuboidal epithelial cells. In PKD, the kidney enlarges and fills with strangulating cysts thought to result from an overproliferation of those epithelial cells. Could it be that malfunctioning cilia on those cells play a causative role? It's beginning to look that way.

Intraflagellar transport, known to be essential for the assembly and maintenance of cilia, may have far-reaching effects that researchers are only just beginning to discover.

Ben Margolis, an HHMI alumni investigator at the University of Michigan, is a nephrologist who studies polarization of epithelial cells in the kidney. He's interested in knowing why those cells lining the ducts are specifically oriented so that the apical side, where the cilium is located, is exposed to urine flow while the opposite, or basolateral, side is exposed to blood.

"Cilia must point into the urine space," says Margolis. "The model is that urine flow bends the cilia, which send some kind of signal to tell the cell there's flow, and that this somehow inhibits cyst formation. Nobody is clear exactly how that happens."

Margolis became intrigued with the role of cilia in cyst formation through discussions with fellow University of Michigan researcher Friedhelm Hildebrandt, who studies a cystic disease in children called nephronophthisis, which is a much rarer condition than PKD but one that appears to be cilia-dependent.

Taking a closer look at one of their apical polarity proteins—called Crumbs—Margolis was surprised to see how it distributed itself. "It was on the apical surface and then it seemed to enter into the cilia," he says. "And it wasn't just in the cilium; it occurred in discrete punctate spots, which is consistent with the intraflagellar transport process in which seemingly large particles of material are moving along the cilium."

When Margolis knocked out the gene for Crumbs3 in cultured kidney cells, no cilia formed. And he found similar results with another family of proteins—called Par—that controls apical/basolateral polarity. Interestingly, Margolis points out, the Crumbs1 gene (closely related to the Crumbs3 gene) is linked to retinitis pigmentosa, a disease associated with defects in intraciliary transport. "We feel that the Crumbs protein can somehow regulate or have an important role in cilia formation," he says. "We're working to identify what that role is."

Iowa researcher Sheffield first started studying the genetics of BBS in 1993. Analyzing the DNA from three large families of Bedouin Arabs with BBS-like symptoms, Sheffield's lab came up with a surprising result: Each of the families mapped to a different place in the genome. "That told us this was a genetically heterogeneous disorder, which other groups' work has since confirmed," says Sheffield. "To make a long story short, eight genes at eight different loci have been identified, and five of those came out of our laboratory."

He thinks the number of BBS genes won't stop at eight, and the search continues in his and other labs. Meanwhile, there is the question of what unifying disease mechanism might link all these genes. By applying the power of bioinformatics, scientists have identified at least one common thread: cilia.

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