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Cilia Malfunction Disrupts Brain Development: Study Helps Explain Joubert Syndrome, Other Disorders

For release: Friday, November 16, 2007

What goes wrong in developmental brain disorders?  Recent genetic studies have suggested a surprising culprit in some of these disorders:  abnormalities in hairlike structures called cilia on the surfaces of cells.  A new study shows that proteins associated with cilia are essential for normal development of the brain’s cerebellum.  The finding helps to explain a diverse and puzzling group of developmental disorders.

Almost all cells have cilia, but until recently, few scientists questioned what they were doing in the nervous system. Some cilia beat rhythmically and allow single-celled creatures such as paramecia to move. These motile cilia are also found in larger organisms, including humans.  For example, motile cilia are found in the lining of respiratory and reproductive systems and in cells lining the fluid-filled brain ventricles. However, most neurons contain cilia that do not move (non-motile cilia). Both motile and non-motile cilia contain receptors that can help cells sense substances in the surrounding environment. 

Cilia have a characteristic structure that includes tiny fibers called microtubules.  Substances called intraflagellar transport proteins (IFT) help to move chemicals along the microtubules from the tips of cilia to their bases inside the cell.  Some substances also move in the opposite direction, from the cells to the tips of the cilia.  Scientists are learning that this transport system helps to control many of the body's functions, including the generation and migration of neurons in the brain.  Disorders caused by abnormal cilia are sometimes referred to as "ciliopathies."   

Recent studies found mutations in cilia-related genes in disorders that include cerebellar malformations, suggesting that cilia might be important for cerebellar development.  However, until now their exact role in the process of cerebellar formation was unclear. The cerebellum is found at the base of the brain, next to the brainstem.  It helps to coordinate movement and sensory perception and contributes to attention, learning, and language.  A number of developmental disorders, including Joubert syndrome, Meckel-Gruber syndrome and Bardet-Biedl syndrome, include defects in this region.  The cerebellum is home to numerous granule cells, which make up more than 50 percent of all the neurons in the brain.  It also contains Purkinje cells - large, complex neurons that control motor coordination.  The neurons develop from cells called progenitors.

To learn how cilia affect cerebellar development, Victor Chizhikov, Ph.D. and Kathleen Millen, Ph.D., at the University of Chicago, in collaboration with researchers from several other institutions,studied mice that had genes for two different cilia proteins inactivated in the nervous system but not in other parts of the body.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the September 5, 2007, issue of The Journal of Neuroscience.[1]

Mice lacking either of the two cilia genes lost their cerebellar cilia and had much smaller cerebellums than normal mice from the same litter, the researchers found.  They also showed severe ataxia, or uncoordinated movements, and most died before they were weaned.  The brains of the affected mice had many fewer granule cells than normal mice.  They also had abnormal-looking Purkinje cells and abnormal Bergmann glia – cells that help granule cells find their correct locations during brain development. 

"The cerebellum normally explodes with growth due to proliferation of granule cell progenitors," says Dr. Millen, the senior author of the study.  "In these mice, there was no massive growth phase.  The development of the cerebellum was interrupted."  The study is the first to show that cilia proteins are required for normal development of the cerebellum.

Additional research showed that the loss of the cilia genes prevented granule cell progenitors from responding to a signaling protein called sonic hedgehog.  This protein controls many functions in the human body, from correct development of fingers to organizing the brain.  It also helps to guide axons and control the division of stem cells. Mutations in sonic hedgehog were previously linked to abnormal cerebellar development.  Mice in the new study had normal sonic hedgehog proteins.  However, the cells weren't 'seeing' sonic hedgehog, so they didn't get the signal to grow. "The findings support an emerging view that cilia serve as tiny sensors of the environment," says Dr. Millen. 

Mutations that completely prevent cilia from functioning have not been reported in any human disorder and are likely to be incompatible with life, Dr. Millen says. To more closely model human disease,the researchers also studied mice with partial impairment of the cilia gene IFT88.  They found that most of these mice had abnormal cerebellums, although some were much more normal than others. The variability of cerebellar malformations in the mice is similar to Joubert syndrome, in which the degree of cerebellar abnormality varies widely, even within families.  Differences in other genes that interact with cilia proteins probably explain this variability, Dr. Millen suggests.  By breeding IFT88 mutant mice with normal mice, they showed that other genes can modify the effect of abnormal IFT88

“This is a very nice story. The role of cilia in neural development has been missing. Dr. Millen’s work shows that its study is very important for researchers studying the cerebellum from both basic and clinical perspectives,” says Robert Riddle, Ph.D., the NINDS program director for the grant that funded this work.

The new study helps explain how things go wrong in some human cerebellar disorders, and the results may lead to eventual development of a therapy to correct these abnormalities."We still, however, have lots of fundamental work to do," Dr. Millen says. Researchers need to learn how cilia work in other types of brain cells and how receptor proteins on the cilia help cells function.  Studying mice with cilia gene abnormalities may lead to discovery of genes that can modify cilia-related signaling. This may provide new insights about how other types of brain disorders develop in humans and may eventually lead to ways of preventing them.

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system.  The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services.  It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-by Natalie Frazin

[1]Chizhikov VV, Davenport J, Zhang Q, Shih EK, Cabello OA, Fuchs J, Yoder BK, Millen KJ.  “Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool.”  The Journal of Neuroscience, September 5, 2007, Vol. 27, No. 36, pp. 9780 –9789.

Last Modified November 16, 2007