An aquarium fish that has delighted grade-school science students with its see-through anatomy also is providing grown-up scholars with a unique window for understanding how embryos emerge from eggs and develop into recognizable creatures.

Of more immediate interest to the medical world, some of these researchers have used the tiny critters to track down genes responsible for human developmental disorders.

In little over a decade, researchers using the tools of modern molecular biology have unearthed a scientific treasure trove in the form of genes that govern the formation of tissues in the one-to-two-inch zebrafish, a native of India's Ganges River now available in most US pet stores. Developmental biologists have warmed to zebrafish study for several reasons, according to UCSF's Didier Stainier, one of three leading developmental biologists who will bring their zebrafish studies to UCSF's new Genetics, Development and Behavioral Sciences research building at Mission Bay.

Zebrafish eggs are externally fertilized and the embryos develop quickly. But to an untrained observer, who peers at developing zebrafish through a low-powered light microscope, their most obvious distinction is that the live-born embryos are beautifully transparent, looking like artful etchings. The normal or abnormal development of their vital organs is vividly displayed.

In addition, Stainier, associate professor of biochemistry and biophysics, notes, "Because it is easy to generate and screen for mutations that affect form and function, the zebrafish is proving to be a uniquely powerful model for the study of vertebrate development."

Stainier's lab team has found several zebrafish mutations that result in heart defects. The researchers also determined that the human counterpart of one of these mutated zebrafish genes may result in a heart condition called hypertrophic cardiomyopathy, the most common cause of sudden death in young athletes.

Zebrafish also are proving valuable in studying the nervous system. Herwig Baier, another UCSF zebrafish research pioneer, is searching for genes that play a role in visual perception. Baier first will look for genes affecting two different behaviors that can easily be elicited by exposing the fish to computer videos. (See related video - QuickTime required.) The first behavior is an "opto-motor" response that enables the fish to use visual cues to remain stationary in a moving stream by swimming in place, something like a treadmill runner in the gym. Baier simulates a moving stream on video with a field of vertical stripes that moves across the screen. The fish larvae vigorously swim with the perceived motion. The second behavior Baier will monitor in his search for telltale genetic abnormalities is the so-called "optokinetic" tracking behavior — the movement of the eye to follow an object.

Abnormally behaving clutches of embryos are examined, and the underlying genetic alterations are determined. With an optical microscope, Baier and members of his research group can view changes in calcium levels that signal nerve activity. The researchers also use fluorescent dyes to highlight networks of nerves in the developing fish brain. Eventually, Baier hopes to figure out how a variety of genes play specific roles in visual perception.

The latest addition to UCSF Mission Bay's trio of zebrafish research leaders is Su Guo, who is screening zebrafish for genetic mutations affecting addiction and neurological disorders similar to Parkinson's disease. Both these disorders involve the neurotransmitter molecules dopamine and noradrenaline, as well as nerve cells and circuitry that rely on these neurotransmitters to receive and send signals. Like Baier, Guo has developed ways to assess fish behavior and relate it to genetic mutations that may underlie the behaviors. For instance, zebrafish quickly develop a fondness for cocaine in their water and move toward it, but some mutants may show little interest.

"Our research will not only provide important insights into how these fundamental neurotransmitter systems work," Guo says, "but also may help to define the causes of dopamine and noradrenaline-related disorders such as Parkinson's disease, sleep disorders, depression, schizophrenia, and addictions, and it may lead to therapeutic interventions for these disorders."

Source: Jeff Norris

Last updated January 27, 2006

Didier Stainier

Didier Stainier will continue his research on zebrafish, a powerful model for the study of vertebrate development, at the UCSF Mission Bay campus. Photo by David Powers.