International research team discovers genetic dysfunction connected to hydrocephalus

PUBLIC RELEASE DATE:

17-Jul-2014

Contact: Jeannette Spalding jeannette.spalding@case.edu 216-368-3004 Case Western Reserve University

The mysterious condition once known as "water on the brain" became just a bit less murky this week thanks to a global research group led in part by a Case Western Reserve researcher. Professor Anthony Wynshaw-Boris, MD, PhD, is the co-principal investigator on a study that illustrates how the domino effect of one genetic error can contribute to excessive cerebrospinal fluid surrounding the brains of mice a disorder known as hydrocephalus. The findings appear online July 17 in the journal Neuron.

Cerebrospinal fluid provides a cushion between the organ and the skull, eliminating waste and performing other functions essential to neurological health. Within the brain there are four spaces or ventricles where cerebrospinal fluid flows. Hydrocephalus can be damaging when excessive cerebrospinal fluid widens spaces between ventricles and creates pressure to brain tissue. In humans, hydrocephalus can cause a host of neurological ailments: impairment of balance and coordination, memory loss, headaches and blurred vision, and even damage to the brain.

"Most of the time, hydrocephalus is caused by some sort of physical blockage of the flow of cerebrospinal fluid, so called obstructive hydrocephalus. We demonstrated instead that malfunction of specific genes the Dishevelleds (Dvl genes) triggered hydrocephalus in our mouse models. These genes regulate the precise placement and alignment of cilia within ependymal cells that move cerebrospinal fluid throughout the brain," said Wynshaw-Boris, MD, PhD, James H. Jewell MD '34 Professor of Genetics and Chair, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine. "This discovery paves the way for more focused research to determine if similar mechanisms can cause hydrocephalus in humans."

Scientists are still at the most nascent stages of understanding different causes and kinds of hydrocephalus. In some instances, the root sources are genetic; in others, the fluid accumulation is attributed to complications of premature birth. This project illuminates one way in which genetic influences contribute to the condition.

Wynshaw-Boris began this collaborative research while a professor in pediatrics at the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California at San Francisco (UCSF) before coming to Case Western Reserve in June 2013. For this hydrocephalus project, he joined fellow principal co-investigator, Arturo Alvarez-Buylla, PhD, professor of neurological surgery, and the Heather and Melanie Muss Endowed Chair, Department of Neurological Surgery, UCSF, in conducting research that proved in mice that Dvl genes regulate the placement and polarity of cilia in ependymal cells that line the ventricles of the brain.

A cilium is a slender protuberance projecting from many cells. In the ependymal cells, multiple cilia protrude from each cell as a bundle or patch, which resembles a horse's tail when beating to move cerebrospinal fluid efficiently. Each cilium must be anchored, sized and shaped correctly, properly placed and aligned in relation to other cilia within the same cell, and the alignment of cilia between cells is also necessary so that the cilia beat with precision to achieve proper movement of fluid in the right direction. It is all about excellent organization: the wrong size, shape or angle of rotation of the bundle of cilia will impede the smooth and appropriate directional flow of the cerebrospinal fluid.

The work in mice by Shinya Ohata, PhD, and Jin Nakatani, PhD, co-first authors who worked in the Alvarez-Buylla and Wynshaw-Boris labs, respectively, and their colleagues demonstrated how normal versus Dvl-deficient mice fared in terms of cilia function. They examined cilia from the ependymal cells of normal mice and found the cilia to be well organized and correctly placed within and between ependymal cells. Investigators even viewed in real time through fluorescent imaging the intricacy with which well-orchestrated cilia swayed to move fluid along in a normal fashion.

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International research team discovers genetic dysfunction connected to hydrocephalus