The long term goal of this project is to develop zebrafish, Brachydanio rerio, as a high-connectivity-model vertebrate organism for biomedical research. Fish have several outstanding qualities for development as a high-connectivity model system for studies in developmental genetics and studies of diseases affecting genes that control growth that control growth and development in vertebrates. The attractive qualities of zebrafish include the following: 1) The zebrafish embryo can be easily examined as it develops in a transplant sac outside of its mother with very little care. 2) The fish egg can be easily manipulated to develop gynogenetically to yield homozygous offspring. 3) Fish are simpler vertebrates than mammals. 4) Effects of abnormal gene expression can be studied in transgenic fish which are easy to produce in large numbers at low cost. 5) Zebrafish eggs can be produced in relatively large numbers on almost a daily basis; the eggs are transparent and easy to microinject. 6) Zebrafish mature in about 4 months, thus facilitating genetic analysis of offspring at the same rate as in mice. To demonstrate the power of using zebrafish as a model system, regulation of the thyroid hormone receptor (c-erbA) gene(s) of zebrafish will be investigated and characterized. Regulation of c-erbA gene expression its critical in normal development in all vertebrates, including humans. Investigations into the complex interactions of c-erbA in the normal physiology of mammalian development may be greatly assisted by a simpler vertebrate system that permits examination of c-erbA expression during early development that is obscured in mammals. Moreover, since fish are not warm-blooded, the role of c-erbA in thermogenesis may be avoided in this organism thereby simplifying analyses. Early embryonic development is well studied in zebrafish, giving us a solid foundation on which to base our investigation. The goals are designed to 1) to examine the c-erbA gene family of fish in order to help clarify the roles the product of this gene plays in vertebrate development, and 2) to investigate the effects of abnormal expression of c-erbA that might be applicable to both thyroid disease and to oncogenesis.
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