A Mother Lode of Mutant Fish

Researchers this month are announcing the first major findings from an international project to generate thousands of mutant zebrafish with telltale embryonic defects. The faulty fish are expected to yield fundamental insights into embryogenesis, the process by which an organism's genetic blueprint unfolds into a body that can slither, swim, or saunter.

The zebrafish project mimics the "saturation screen" of fruit fly embryos carried out by developmental geneticists Christiane Nüsslein-Volhard at the Max Planck Institute for Developmental Biology in Tübingen, Germany, and Princeton's Eric Wieschaus in the late 1970s. That screen, in which the researchers randomly mutated the DNA of thousands of fruit flies and then screened their offspring for embryonic defects, opened the door on the molecular events behind fly development and won the pair a Nobel Prize in physiology or medicine in 1995. Hoping to repeat that success in a vertebrate organism, two laboratories led by Nüsslein-Volhard and Wolfgang Driever at Boston's Massachusetts General Hospital turned to the striped, inch-long zebrafish Danio rerio, a fast-breeding, freshwater aquarium species.

Filling the entire December issue of the journal Development, Nüsslein-Volhard's and Driever's groups describe new mutant strains with congenital flaws ranging from brainlessness to taillessness and from hyperactivity to slothfulness (Science, 6 December, p. 1608). "Our mutations affect some of the very earliest processes in development," says Nüsslein-Volhard. "We hope this will open up new areas of research."

By exposing hundreds of male zebrafish to a chemical that can disable genes in the fish's sperm and examining embryos produced by their descendants, the two labs have built a bank of 2000 fish stocks carrying mutations in some 600 genes. Mutant embryos named sleepy, grumpy, and bashful, for example, lack the cells containing bubbles or "vacuoles" that normally stiffen the notochord, a rodlike support structure. In these dwarf mutants, the genes controlling crucial steps in the program that causes notochord cells to differentiate may be disrupted, says Derek Stemple, a postdoctoral researcher in Driever's lab.

"To depict the embryo in terms of networks of gene expression is a very ambitious goal," says Hazel Sive, a molecular embryologist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. "But this is a very exciting set of mutants."