Systematic Vertebrate Functional Genomics

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DESCRIPTION (provided by applicant): The vertebrate genome contains a predicted 30,000+ genes, most of unknown function. The annotation of genes is one of the major next steps in understanding the vertebrate genome. The recent development of morpholino-based gene 'knockdown' technology in zebrafish has opened the door to the genome-wide assignment of function based on sequence in a model vertebrate. In this competitive renewal, we will focus on the systematic assignment of biological function to 300 putative secreted proteins to identify new players in these clinically relevant processes. We will accomplish this goal through the following specific aims: Aim I. Development of a secreted protein morpholino core database. Morpholinos targeted to these genes will be generated and examined for function in the following biological processes: Aim II. Isolation of secreted proteins required for embryonic patterning and organogenesis. Aim III. Isolation of secreted proteins required for cardiovascular and sensory organ formation. Aim IV. Isolation of secreted proteins required for digestive organ formation and function. Aim V. Annotation of the identified phenotypes and incorporation of this gene set information into the international zebrafish database at ZFIN. The identification of molecules required for vertebrate patterning and organ function has critical implications for the understanding of genetic deficiencies in these processes. In addition, the molecules identified as crucial for development in vivo will serve as key substrate molecules for potential small molecule drug target intervention and for the establishment of conditions for stem cell manipulation such as in vitro organ formation. The zebrafish offers the first opportunity for a comprehensive analysis of these processes using as template an entire vertebrate genome.