Researchers at Washington University School of Medicine, in St. Louis, have identified a gene that is required for proper development of the mouse inner ear. In humans the FGF20 gene is located in a portion of the genome that has been associated with inherited deafness in otherwise healthy families (PLoS Biology, online, Jan. 3, 2012).
"When we inactivated FGF20 in mice, we saw they were alive and healthy," said senior author David Ornitz, MD, PhD, professor of developmental biology. "But then we figured out that they had absolutely no ability to hear."
Results of the new study show that disabling the gene causes a loss of outer hair cells. While about two-thirds of the outer hair cells were missing in mice without FGF20, the number of inner hair cells appeared normal.
"This is the first evidence that inner and outer hair cells develop independently of one another," said first author Sung-Ho Huh, PhD, a postdoctoral research associate. "This is important because most age-related and noise-induced hearing loss is due to the loss of outer hair cells."
The researchers speculate that FGF20 signaling will be a required step toward the goal of regenerating outer hair cells in mammals, the only vertebrates incapable of such feats of hearing restoration.
"All vertebrates other than mammals have the ability to regenerate hair cells," said co-author Mark Warchol, PhD, professor of otolaryngology. "Understanding how mammals differ from the rest is a topic of great interest."
The FGF20 gene codes for one member of a family of proteins known as fibroblast growth factors (FGF). Members of this family generally play important and broad roles in embryonic development, tissue maintenance and wound healing.
Beyond a simple on-and-off switch, Dr. Ornitz and his colleagues found that FGF20 signaling - or FGF9, its chemical equivalent - must occur on or before day 14 of the embryo's development to produce a normal inner ear. Even if FGF20 or FGF9 signaling occurred on day 15 or later, the inner ear still did not develop properly.
"In mice the precursor cells that can become outer hair cells must be exposed to the FGF20 protein at an early stage," Dr. Ornitz said. "After embryonic day 14 it doesn't matter if they see the protein. It's too late for them to become outer hair cells."
This critical time point does not exist in other vertebrates that retain the ability to form new hair cells throughout their lives. Whether FGF20 plays a role in this regeneration remains an open question.
"We're doing those experiments right now," Dr. Warchol said. "But FGF20 has been shown to be involved in other kinds of regeneration like the regrowth of zebrafish fins."
The researchers also see evidence that mutations in FGF20 may play a role in human deafness. A genetic region known as DFNB71 has been associated with congenital deafness in a few human families.
"FGF20 is right in the center of that region," Dr. Ornitz said. "Based on our work, we are predicting that these families will have some sort of mutation in the FGF20 gene. It hasn't been found yet, but a group at the Baylor College of Medicine is sequencing this region of the genome to look for FGF20 gene mutations."
The study was funded by the Washington University Department of Developmental Biology, the Hearing Health Foundation, and Action on Hearing Loss Foundation, with contributions from Edward and Linda Ornitz and grants from the National Institute on Deafness and Other Communication Disorders and the National Institutes of Health.