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September 3, 2004|Volume 33, Number 2|Two-Week Issue



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Studies demonstrate role
of cilia in kidney disease

Studies on a single-celled alga are providing Yale researchers unexpected insights into kidney disease.

Cilia and flagella are hair-like filaments located on the surface of many types of cells, including the one-celled green alga Chlamydomonas and kidney tubule cells. Most cilia can move, and propel fluid across cell surfaces. The flagella of Chlamydomonas are "tails" that drive the algae. However, many cilia -- including those on kidney tubule cells -- do not move on their own. In fact, most textbooks describe kidney cilia as being "vestigial" or "of unknown function."

This is no longer a valid idea, according to reports from Joel Rosenbaum, professor of molecular, cellular and developmental biology (MCDB) at Yale, and his colleagues Greg Pazour and George Witman, at the University of Massachusetts Medical Center. The researchers have showed that the human kidney disease, autosomal dominant polycystic kidney disease (AD-PKD) is linked to the function of kidney cilia.

AD-PKD is the most common, life-threatening genetic disease in humans -- it affects one in every 500 people. More than 600,000 Americans and an estimated 12.5 million people worldwide have AD-PKD. The disease is characterized by uncontrolled epithelial cell division that leads to formation of large cysts and kidney failure. Approximately 50% of the affected people have end-stage kidney disease by the age of 60.

The key genes responsible for AD-PKD were cloned and characterized at the School of Medicine by Stefan Somlo, the C.N.H. Long Professor of Internal Medicine (Nephrology), and his research group. Along with colleagues in the laboratory of Barbara Ehrlich, professor of pharmacology and physiology, the researchers showed that these genes encoded two membrane proteins -- polycystin 1 and 2 ion channels -- that cooperate in the movement of calcium across membranes.

On the other side of campus, Rosenbaum's group in MCDB studies how the flagella of Chlamydomonas are assembled. Their work was the first to show that flagella form using a process termed intraflagellar transport (IFT), and that genes coding for the IFT process are active in all cells that have cilia or flagella. When IFT genes are defective, flagella (or cilia) do not form properly.

When Rosenbaum's group searched gene sequence databases for similar genes, they were surprised to find that one of the IFT genes they had cloned and sequenced from the alga was nearly identical to a gene previously identified in the mouse -- and that mice with mutations in that gene developed AD-PKD.

Rosenbaum and his colleagues then looked at cells from the kidneys of mice with AD-PKD using electron microscopy. They found that the cilia they observed were either abnormally short or missing.

The link between AD-PKD and kidney cilia was strengthened when the defective polycystins were localized, in large part, on the kidney cilia. Apparently, AD-PKD could develop either from defects in the polycystin proteins themselves, or from an inability to form normal cilia, where some of these channels normally reside.

The importance of cilia for kidney function was shown in studies by investigators at the National Institutes of Health (NIH), at Harvard Medical School and Yale by Somlo and Michael Caplan, professor of physiology and cell biology.

Their research showed that mechanical movement of the kidney cilia causes calcium to flow into kidney cells, and that the calcium almost certainly travels through polycystin ion channels on the cilia. When the polycystins on the cilia were either missing or defective there was no calcium flow. This suggested to the researchers that the kidney cilia most likely act as mechanical sensors -- that they respond to fluid flow in the kidney tubules by bending and passing calcium through the polycystin channels on their surface.

Current research focuses on how this calcium flow is related to the uncontrolled cell division characteristic of AD-PKD. At the November 2003 American Society of Nephrology, Caplan and Somlo reported that when kidney cilia are mechanically bent and calcium flows into the cells, a piece of the calcium channel protein polycystin 1 is clipped off and relocates to the cell nucleus. In the nucleus, the protein fragment alters the regulation of expression of particular genes.

Genetic studies on the worm, C. elegans, by another of Rosenbaum's colleagues -- Maureen Barr at the University of Wisconsin -- also helped define the relationship between cilia and AD-PKD. In these worms, the cilia function as sensory organelles. Their cilia also contain the polycystin 1 and 2 channels. The worm's capacity to sense its surroundings can be affected either by mutations in the channels themselves or by mutations in the IFT process and the ability to form the sensory cilia.

This recent work demonstrates a direct link between the mechano-sensory calcium channels on the cilia and nuclear gene regulation in kidney cells, say the researchers, and it is some of the first evidence linking the function of polycystin ion channels to the transcription of messenger RNA from the nuclear genome. It is likely that these genes control signaling events in the cell that control kidney cell division, they say.

The participation of cilia in AD-PKD is now called "The Ciliary Hypothesis of AD-PKD."

The work on AD-PKD is supported by grants from the NIH. Rosenbaum recently received an NIH MERIT award grant totaling $4.5 million for studies on the role of cilia in disease.

-- By Janet Rettig Emanuel


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Hockfield is appointed as MIT president

Changes to improve campus shuttle's efficiency

China's education leaders learn about Yale

FRESHMAN ADDRESSES

Nursing dean Catherine Gilliss accepts dual post at Duke

Law student makes wrestling history . . .

Graduate School's 522 new members welcomed . . .

Yale to be test site for national study on childhood epilepsy

In Focus: Studying the Near East

Desert expeditions challenge previous notions
about early societies


Year's first Chubb Lecture to explore ethical issues and Olympics

Studies demonstrate role of cilia in kidney disease

Yale researchers' studies of mental illness win grant support

Historic events in psychology to be celebrated

Jewish philosopher Maimonides is the subject of conference

Film Fest New Haven to feature four works by Yale alumni

While You Were Away: The summer's top stories revisited

Welcome to Yale

Yale United Way Campaign sponsoring 'Day of Caring' book drive

In Memoriam: Mathematician Walter Feit, advanced finite group theory

Memorial Service for John Rodgers

Symposium honors Dr. Charles Radding

Historian is term member of foreign relations council

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