Followup study finds gene knockout has different effects in specific areas of inner ear
Massachusetts General Hospital (MGH) researchers have made important progress in their ongoing effort to regenerate the inner ear's hair cells, which convert sound vibrations to nerve impulses. In an upcoming issue of Proceeding of the National Academy of Sciences they report successfully creating a mouse model that allows them to build on earlier findings about the effect of deactivating a protein that controls the growth and division of hair cells. The paper, which is receiving early online publication, also finds that suppressing the retinoblastoma (Rb) protein has different effects in specific parts of the inner ear.
"In these first studies of the role of the Rb protein in the ears of postnatal mice, we have confirmed that - under the right conditions - mature hair cells can go through the cell cycle and produce new, functioning hair cells. But we've also confirmed that you need to block Rb reversibly and at an early stage of development, otherwise the hair cells will die," says Zheng-Yi Chen, DPhil, of the MGH Neurology Service, the study's senior author. In 2005 Chen was named to the Scientific American 50, the magazine's annual list of outstanding leaders, for this continuing research project.
Named for the hair-like projections on their surfaces, hair cells form a ribbon of vibration sensors along the length of the cochlea - the organ of the inner ear that senses sound - where they convert sonic vibrations to electrical signals that are carried to the brain. The cells are very sensitive to damage from excessive noise, infections and toxins. Once damaged, hair cells do not naturally regenerate in mammals, and their death accounts for most types of acquired hearing loss.
All cells grow and divide through a process called the cell cycle, and many proteins have been identified that control different cell cycle phases. In 2005 Chen's group published a paper in the journal Science reporting that the Rb protein, known to suppress the cell cycle, could be important for halting the cell cycle in hair cells. They used a genetically modified mouse strain in which Rb was no longer made in the inner ear. By examining the inner ears of mouse embryos - that strain did not survive past birth - the researchers found more hair cells in the knockout mice than in the ears of normal mice at the same stage of development. The additional cells looked and functioned like normal hair cells and appeared to be actively regenerating.
For this followup study, the researchers developed a new strain of inner-ear Rb-knockout mice that survive for up to six months past birth. Their investigation of the effects of Rb deletion on the hair cells of the inner ear finds differences between the auditory portion of the organ, which controls hearing, and the vestibular area, which is involved with balance. While the Rb-negative auditory hair cells in early postnatal mice are dividing and growing, the cells do not mature properly and eventually die, resulting in the mice becoming deaf by the age of 3 months. Vestibular hair cells, however, appear to grow and mature relatively normally and continue cell division even in mature mice. Adult Rb-knockout mice maintain some vestibular function, indicating that those hair cells are contributing to their sense of balance at the system level.
"We've shown that vestibular hair cell regeneration may be achieved and may be less of an obstacle than auditory cell regeneration," Chen says. "Now we need to find ways to create a similar system in the auditory cells, and this new model will help us better understand the mechanisms behind functional hair cell regeneration. Our next step will be developing a transient, reversible block of Rb function to assess its role in both types of hair cell." Chen is an assistant professor of Neurology of Harvard Medical School (HMS).
The report's co-authors are first author Cyrille Sage, PhD, and Mingqian Huang, PhD, of the MGH; Melissa Vollrath, PhD, and David Corey, PhD, Howard Hughes Medical Institute and HMS; M. Christian Brown, PhD, Mass. Eye and Ear Infirmary; Douglas E. Vetter, PhD, and Philip Hinds, PhD, Tufts-New England Medical Center. The research was supported by grants from the National Institutes of Health, the Howard Hughes Medical Institute and a Pfizer/AFAR Innovations in Aging Research Grant.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Taken from www.eurekalert.org/pub_releases/2006-04/mgh-rlm042806.php
