Novel Gene Found Critical for Regeneration in Zebrafish

Novel Gene Found Critical for Regeneration in Zebrafish

Humans owe their senses of balance and hearing to microscopic vibration detectors called hair cells, which are located deep within the inner ear. These sensitive structures send messages to the brain that are interpreted as sound and spatial orientation. If hair cells are destroyed by disease or injury, humans suffer permanent hearing loss. But some of our fellow vertebrates are much more fortunate, with fish, amphibians, reptiles and birds all possessing the ability to regenerate damaged hair cells.

Now, as part of their ongoing effort to unlock the secrets of these amazing regenerative powers, National Human Genome Research Institute (NHGRI) researchers have identified a gene that plays a crucial role in hair cell regeneration in zebrafish. They call the gene phoenix, a reference to the mythical firebird that after being consumed by flames, arises anew from the ashes.

A small species often found in aquariums, zebrafish offer many useful features for biological and genomic research. These fish reproduce at a rapid rate, share many of the same genes with humans, have transparent offspring, and can be genetically manipulated for research studies.

Published in the April 17 edition of the online journal PLoS Genetics, the NHGRI study found that when the phoenix gene is mutated, zebrafish lose their ability to regenerate hair cells in their lateral line. The lateral line is an organ related to our inner ear that runs along the sides of fish and amphibians, providing them with sensory signals that help them detect prey, avoid predators, find mates and swim in schools.

"It remains to be discovered whether mammals have a similar gene in their genome," said senior author Shawn Burgess, Ph.D., a senior investigator in NHGRI's Genome Technology Branch. "But it is very compelling to consider the implications of this research related to the possibility of restoring human hearing and balance through regeneration."

The researchers began their study by closely looking at a mutated strain of zebrafish. These fish do not have any obvious physical or behavioral defects, and, like other zebrafish, can regenerate many types of cells in response to injury. However, when the phoenix mutants are exposed to chemicals that destroy the hair cells that make up their lateral line, they cannot regenerate these particular cells like other zebrafish.

After characterizing the precise nature of the regeneration defects in phoenix mutants, the researchers identified the region of the genome harboring the phoenix mutation and then determined the specific gene carrying the defect — a gene they ultimately dubbed phoenix, or pho.

The researchers went on to locate versions of the pho gene in a number of other fish species. They have not yet identified any pho counterparts in other vertebrates. Dr. Burgess says this indicates the gene is evolving rapidly and likely has been greatly modified over time. He further emphasizes that mammals and other vertebrates may still have functionally similar proteins coded by genes or groups of genes that are closely related to pho.