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New NICHD Zebrafish Facility Opens in 6B

By Robert Bock

"I'd like to thank the NICHD's Research Animal Management Branch, NIH's creative and committed Division of Engineering Services, and our own developmental biologists for their contributions to the design elegance and efficiency of this new facility," said NICHD scientific director Dr. Arthur S. Levine recently as he cut the ribbon barring the doorway of the institute's new zebrafish facility. "I'd also like to thank the many others -- too numerous to mention individually -- who also contributed."

Adult zebrafish

Zebrafish, Danio rerio, are kept by home aquarists the world over. In recent years, these small silvery fish with horizontal blue stripes have also become a mainstay of developmental biologists. At the NICHD facility, racks of bookshelf-like trays provide storage space for a battery of clear plastic containers needed to house the inch-and-a-half-long fish. A high-tech filtration system drips a continuous supply of purified water into the containers; electronic sensors carefully control the temperature, pH and salt content of the fish's environment.

Native to the Ganges River and its tributaries in India, zebrafish offer several advantages over other animals that researchers use to study the process by which a fertilized egg develops into an adult individual. Like another staple of developmental biology, the fruitfly (Drosophila melanogaster), zebrafish are easy and comparatively inexpensive to maintain, rapidly produce large numbers of offspring, and have easily studied genetics. But like human beings, zebrafish are vertebrates, and follow the typical vertebrate path of embryonic development. Unlike laboratory mice, another useful developmental biology model, zebrafish eggs and embryos are transparent, develop outside the mother, and so provide a clear, unobstructed view of early embryonic development.

NICHD aquatics technician Alyssa Gundersen inspects the device used to hatch the tiny shrimp that form a mainstay of the zebrafish's diet.

Mutations in zebrafish genes can be created with relative ease. First, the males are exposed to a chemical that causes mutations in the DNA of their sperm. Most of the mutations are recessive and will only cause visible defects if both copies of the gene in each cell are mutated. To achieve this, these males are then mated with genetically normal females, producing offspring with one copy of the resulting genetic defects. Fish from this second generation are then crossed with each other, to produce a third generation with the two copies of a mutated gene needed for the gene's effects to be visible.

Dr. Brant Weinstein, a researcher at NICHD's Laboratory of Molecular Genetics, heads a group of researchers studying a zebrafish mutation known as "gridlock." Fish with this mutation suffer from an obstruction in the circulatory system, in which the aorta (the main vessel leading out of the heart) is foreshortened, depriving the tail region of its blood supply. In fact, fish with the gridlock mutation lack tail fins. Weinstein said that the gridlock mutation resembles a human birth defect, coarctation of the aorta. In coarctation of the aorta, a narrowing of the descending aorta often causes high blood pressure above the narrowing, in the head and neck, and poor circulation below the chest.

A visitor at the NICHD zebrafish facility open house inspects the rows of containers used to house the fish.

"It's a common birth defect, occurring in 1 in 2,000 births," Weinstein said. "In humans, however, we don't know the genetic basis."

Insights gained from studying gridlock, Weinstein hopes, will provide likely candidates to identify the genetic basis of the condition in humans.

Laboratory of Molecular Genetics researcher Dr. Ajay Chitnis heads a group investigating the so-called "notch" receptor, a molecule that sits on the surface of cells in the neural plate, the structure in the zebrafish embryo that eventually gives rise to the brain and spinal cord. Ordinarily, the appearance of the notch receptor on the cell's surface allows it to receive chemical signals that tell it to stop dividing and differentiate into a nervous system cell. In a mutation Chitnis is studying, however, the receptor fails to appear on the cell's surface, and the cell fails to develop any further but continues to divide repeatedly. Studies of this and similar mutations, Chitnis said, may provide insight not only into abnormal brain development, but also into the development of some human cancers that have been linked to abnormalities in the notch receptor.

At the ribbon cutting ceremony for the new NICHD zebrafish room are (front row) Doreen Bartlett, animal administrator; Dr. Arthur Levine, NICHD scientific director; Dr. Igor Dawid, chief, Laboratory of Molecular Genetics; and (back row) Anthony Clifford, director, Division of Engineering Services; Rosemary Rigs, animal program administrator; and John Bartholomew, chief, Research Animal Management Branch.

Dr. Igor Dawid, chief of the Laboratory of Molecular Genetics, leads a research team studying zebrafish embryos to learn how the early nervous system develops. One of the projects in Dawid's group is the study of a transcription factor named lim1, which plays a key role in the early development of the nervous system by controlling generation of a chemical signal that sets the process in motion. By studying transcription factor expression, he and his colleagues have been able to observe exactly when the factor appears during each particular stage of embryonic nervous system development.

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