Yale Bulletin and Calendar

December 1, 2006|Volume 35, Number 12|Two-Week Issue

Joel Rosenbaum

Yale cell biologist is honored for
his research with Wilson Medal

Joel Rosenbaum, professor in the Department of Molecular, Cellular and Developmental Biology (MCDB) and a faculty member at Yale since 1967, has been named the recipient of the 2006 E.B. Wilson Medal, the American Society for Cell Biology's highest honor for scientific research in cell biology.

The medal will be presented to Rosenbaum for significant advances over a lifetime on the assembly, maintenance and function of fine, hair-like cell organelles called cilia (or also known as flagella), which extend from the cell surface.

Recently, Rosenbaum and his students and colleagues have shown that the cilia are fundamental to the pathogenesis of one of the most prevalent of human diseases, polycystic kidney disease (PKD), forms of which can affect as many as one in 500 people.

Rosenbaum has produced much of his groundbreaking research by studying cilia in single-celled protistans, principally the bi-flagellate alga, Chlamydomonas. Cilia are best studied in organisms like Chlamydomonas because their structure has been conserved even to humans, and they can be grown in quantity to isolate flagella in large amounts. Further, their cell division is easily synchronized and the genome sequence of Chlamydomonas and the flagellar "proteome," or complete catalogue of proteins, has been published.

Using this organism, Rosenbaum designed systems to study flagellar growth and regeneration. In some of his initial studies as a postdoctoral fellow at the University of Chicago, he showed that flagella grew and elongated by adding on new subunits to their tips, distant from the cell body where the flagellar proteins are synthesized.

When listening to Rosenbaum present his "flagellar tip growth" research in the mid-1970s, former Yale professor and Nobel laureate George Palade suggested that there "must be elevators in the flagella" carrying subunits from their site of synthesis in the cell body to the tip of the flagella where assembly takes place.

In 1992, using new high-resolution microscopes, Rosenbaum's graduate student, Keith Kozminski, was first able to observe these "elevators." He saw particles moving up and down the length of the flagella, between the membrane and the microtubule-based core of the flagella. The researchers named the process intraflagellar transport (IFT).

These initial observations led to biochemical and genetic studies showing that molecular motors controlled movement of the IFT particles. When the motors were stopped, flagella would not form, and already-formed flagella became shorter. They also showed that the IFT particles served as transports, carrying prefabricated parts of the flagellar core to the tip for assembly and recycling turnover products from the tip back to the cell body. Over the next several years, IFT particles were isolated, their polypeptides were identified and many of the genes for IFT were cloned.

When the IFT genes were compared with the various available "on line" gene libraries, they were surprised to find that a sequence matching one Chlamydomonas IFT gene, called "IFT88," was in the mouse genome and was the gene which was defective in the then-current mouse model of PKD.

The relationship between an IFT particle gene that would block flagella assembly in Chlamydomonas when mutated and produce PKD in the mouse model seemed remote. Few researchers had paid attention to the fact that the cells forming the kidney tubules each had a single non-motile "primary" cilium pointing toward the center of the tubule.

When Rosenbaum and his colleagues Gregory Pazour and George Witman at University of Massachusetts Medical School examined kidney tubules of the PKD mutant mouse with the scanning electron microscope, they found that the cilia were either short or missing. They also provided conclusive evidence for the importance of cilia in the PKD pathology by demonstrating that the polycystins, gene products of the PKD genes, were located on these cilia. Because cilia were related directly to the disease, this became known as the "ciliary hypothesis of PKD."

"Researchers at the NIH [National Institutes of Health] and Yale medical school have now shown that these cilia bend when urine flows down the tubules, admitting calcium through the polycystins, which are mechano-receptors in the ciliary membrane. Through a signaling pathway, the calcium represses cell division," says Rosenbaum. "If calcium does not flow in, because the cilia are missing or the polycystins on the membrane are missing or ineffective, a signal is sent to the nucleus and the tubule cells divide -- and continue to divide. PKD is, therefore, a cancer of the kidney, where cells that should not be dividing start to divide because of a defect in a signaling pathway starting at the cilium."

This sensory role of primary non-motile cilia has now become the model for many other diseases and syndromes, all of which trace back in many different tissues to defects in receptors or channels on the ciliary membrane or to the complete lack of the cilium due to a defect in the IFT process.

Rosenbaum's laboratory is now working on the connection between cilia and the cell cycle. Their latest work shows that when the amount of one of the IFT polypeptides, a small G protein, is decreased, the cell cycle is severely inhibited.

This IFT small G protein is a direct link between cilia and the cell cycle. In a normal cell cycle, the protein decreases, taking all the other IFT polypeptides with it, causing the cilia to shorten and permitting the ciliary basal bodies/centrioles to migrate to the center of the cell to form the mitotic apparatus. Following chromosome separation, the amount of this IFT protein again increases and the cell divides. If the amount of the IFT protein is kept low experimentally, the cells will not divide and will die.

Understanding the IFT process has also led to discoveries on causes of conditions like situs inversus, a condition in which the heart or other organs grow on the wrong side of the body's midline during embryonic development. Rosenbaum's colleague in pediatric cardiology, associate professor Martina Brueckner, has shown that the presence of cilia in the embryonic nodal region is directly related to this condition: If the cilia are missing or not functioning, situs inversus results. In the mutant mouse with defective or missing cilia, situs inversus occurs as well as PKD in many cases. Many of these mice are also blind, because the rod outer segments of the retina form from cilia during embryogenesis and are maintained in adults by IFT in a piece of the cilium in the adult rod cell.

Finally, a complex of diseases called Bardet-Biedl Syndrome (BBS), which can manifest itself in diabetes, polydactyly and obesity, all stem from defects in the cilia or the ciliary basal body/centriole. "It seems as though each month a new disease is shown to have its origin in these oft-neglected cell organelles," comments Rosenbaum.

Rosenbaum is the seventh member of the Yale faculty to receive the Wilson Medal. In 2005, Joan A. Steitz, Sterling Professor of Molecular Biophysics and Biochemistry and an investigator at the Howard Hughes Medical Institute, received the award for her work on small nuclear ribonucleoproteins. In 2004, Thomas D. Pollard, Sterling Professor and chair of the Department of Molecular, Cellular and Developmental Biology, received the award for his pioneering work on the molecular basis of cell movement. Former Yale faculty who have received the award are George Palade and Marilyn Farquhar (now at the University of California, San Diego), Joseph Gall (now at the Carnegie Institute of Embryology) and Bruce Nicklas (currently at Duke University).

T H I SW E E K ' SS T O R I E S

Yale boasts five Rhodes Scholars

Special events mark reopening of Kahn Building

Fellow scientists honor four Yale researchers as AAAS Fellows

Climbing Iranian peak was 'exercise in citizen diploma

"Arts at Yale"

Amy Meyers is reappointed as museum's director

Expanded program helps physicians meet . . .

Yale cell biologist is honored for his research with Wilson Medal

Yale Rep's 'Black Snow' takes satirical look at life in the theater

Noted author and peace activist Elie Wiesel to give Chubb Lecture

Drama school's 'Zero Hour' recounts student's experience of Bosnian war

Annual educational concert to benefit needy in New Haven

Exhibit chronicles gay, lesbian, bisexual and transgender history

Shopping, anyone?

Campus Notes