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Roundworms offer new insights into Bardet-Biedl syndrome

Using the model organism C. elegans, the researchers showed that a protein complex called BBSome can function outside of cilia. Dysfunctions of this protein complex lead to the human genetic Bardet-Biedl syndrome. Here, BBSome (in green) is enriched at the tip of C. elegan, where the cilia are located, but is also expressed at other cellular locations, including the cell bodies of neurons. Credit: Xinxing Zhang, Ph.D., UM Institute of Life Sciences.

Scientists have identified a new role for a protein complex at the center of a human genetic condition called Bardet-Biedl syndrome, or BBS, for which there is currently no cure.

Bardet-Biedl syndrome occurs when the BBSome protein complex malfunctions. Because the BBSome regulates the form and function of cilia, the hair-like structures on the surface of cells, BBS has been classified as a disease of the eyelashes.

But the wide range of symptoms associated with BBS – the most common of which are loss of vision, as well as obesity, extra fingers or toes, and kidney dysfunction – has led to speculation that the cause of the syndrome does not lie not only in the eyelashes.

In a new study published in Developmental Cell, a team from the University of Michigan’s Institute of Life Sciences now offers the first known direct evidence for these hypotheses. Their findings demonstrate that the BBsome functions outside of the cilia to support sight, at least in a common model species.

The discovery began when scientists in the lab of LSI faculty member Shawn Xu were studying how tiny roundworms called Caenorhabditis elegans can sense light despite lacking eye-like organs. Because C. elegans has a simple, well-mapped nervous system, the Xu lab uses them as a model to understand the basic biology behind various forms of sensation.

The team performed genetic screening, a process of introducing random mutations to identify genes needed for a given biological process, to find the genes involved in the worms’ ability to respond to light. Most of the mutations that prevented the worms from sensing light turned out to be in the BBSome. And, like the progressive vision loss that BBS patients experience, worms with BBSome mutations gradually lost the ability to sense light as they aged.

Through a series of several other experiments, the team discovered that the BBSome plays a role in light sensation independent of its role in eyelashes. In one scenario, they mutated C. elegans to suppress all cilia; in a second experiment, they left the eyelashes on the worms but prevented the BBSome from reaching the eyelashes. In either case, the worms were still able to detect light, as long as the BBSome was functioning in the rest of the cell.

“It’s a great demonstration of the power of model organisms,” said Xinxing Zhang, postdoctoral researcher at the Xu lab and lead author of the study. “Eyelashes are essential for most organisms. But we can remove the cilia from C. elegans and they still survive, allowing us to uncover this unexpected role for the completely cilia-independent BBSome.

Xu’s lab previously found that C. elegans senses light through a receptor protein called LITE-1 that sits on the surface of neurons and sends signals to the central nervous system to respond to light (in the case of worms). , moving away from it).

In this latest study, the team found that when BBSome malfunctions in the cell, LITE-1 receptors are brought back into the cell from the surface and then broken down, preventing the worms from detecting light.

In a second genetic screen, the scientists discovered that the degradation process of LITE-1 is controlled by another protein called DLK. The BBsome prevents DLK from starting a chain reaction that inappropriately breaks down LITE-1.

Both BBSome and DLK are conserved in humans, and researchers were able to show that BBSome similarly blocks DLK expression in human cells. They think this BBSome-DLK-photosensor pathway might be involved in the vision loss so prominent in patients with Bardet-Biedl syndrome.

“Because BBS is known to be caused by defects in the BBSome, it has long been assumed that the disorder must be related to the cilia,” said Xu, who is also a professor of molecular and integrative physiology at UM Medical School. . “We do not dispute that BBS is linked to defects in the eyelashes. We are simply offering direct evidence that the BBSome can also work outside the eyelashes, and that it plays a role there related to light sensation. This may broaden the view of how to develop treatments for BBS. »

This research was supported by the National Institutes of Health.

The study authors are: Xinxing Zhang, Jinzhi Liu, Tong Pan, Alex Ward and XZ Shawn Xu of the University of Michigan; and Jianfeng Liu of Huazhong University of Science and Technology, China. “A cilia-independent function of BBSome mediated by DLK-MAPK signaling in C.elegans photosensation”,Development Cell. 10.1016/j.devcel.2022.05.005

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