Zebrafish Model Human Development And Disease

Among the model systems for studying development, the zebrafish has become prized because its transparent embryo develops outside the mother’s body. The zebrafish has helped biologists identify many genes involved in embryogenesis and, because it’s a vertebrate animal, has become a valuable resource for identifying genes involved in human disease. Zebrafish are the focus of two research articles and an accompanying news feature in this issue of PLoS Biology.

Thomas Bartman and colleagues use the powerful tools afforded by zebrafish genetics to examine the early steps of heart valve formation. In the process, they provide evidence for a causal relationship between the early function of the heart and its final structure. Using a fluorescent molecular marker highly expressed in the developing heart, the authors found mutations that result in valve defects, and identified a fish mutant they named cardiofunk (cfk).

Genetic mapping of cfk showed that the abnormality was caused by a mutation in a gene encoding a novel actin molecule that is most closely related to the actins found in muscle cells. Actin is involved in muscle contraction; so these results suggest that muscle contraction in the embryonic heart is intimately involved in heart development. Blood flow might also be involved, although the authors find that the heart develops normally even in the presence of pharmacological compounds that abolish blood flow. The characterization of additional mutants will shed further light on this issue.

Valve or septal defects represent 40% of cardiac anomalies in humans. Bartman and colleagues suggest that, by analogy with zebrafish, some of these defects may result from congenital defects affecting very early heart function.

Nancy Hopkins of the Massachusetts Institute of Technology is using zebrafish to study cancer. Her group has created over 500 lines of zebrafish with lesions in key genes involved in development and used them to identify a group of genes that predispose the fish to cancer, with some surprising results.

During the process of cultivating some of these mutant lines, the Hopkins team noticed that an abnormally large percentage of fish died young, whereas the surviving fish in these lines developed large, highly invasive malignant tumors. The researchers investigated the genetic makeup of the fish and discovered that many of the lines were heterozygous for a mutation in a different ribosomal protein gene (rp)–that is, each line carried one healthy version and one defective version of a different rp gene. These proteins are components of ribosomes–the massive molecular complexes within cells that mediate protein synthesis–and are essential for embryonic development.

Though it’s not clear what distinguishes the 11 rp genes whose mutations cause cancer from the five other rp genes whose mutations do not, the authors raise a number of possibilities for future study. And given the high degree of conservation of genes and pathways among vertebrates, it’s possible that rp mutations also raise cancer risk in humans. Together, these results demonstrate that the tiny freshwater workhorse of developmental biology has a promising future as a model system for human cancer.

In the accompanying news feature, Jane Bradbury, explores the uses of zebrafish as a model system for vertebrate development and disease, focusing on the ZF-MODELS research consortium which was recently awarded 12 million Euros by the European Union.

citation:
Bartman T, Walsh EC, Wen K-K, McKane M, Ren J, et al. (2004) Early myocardial function affects endocardial cushion development in zebrafish. PLoS Biol 2(5): e129 DOI: 10.1371/journal.pbio.0020129