We study the genetic and evolutionary mechanisms underlying early embryonic development using a combination of molecular genetic and functional genomics approaches in the animal model C. elegans and related nematodes. One of our major goals is to use RNA interference (RNAi) of ovary-expressed genes followed by time-lapse microscopy to work toward a comprehensive molecular description of early embryogenesis in C. elegans. RNAi offers a powerful way to obtain information about the loss-of-function phenotype of the genes tested, while the early embryo offers a system in which basic cellular and developmental processes can be easily studied. We currently have tested over 1,000 genes and identified about 300 genes required for embryogenesis. Although most of these genes are highly conserved, fewer than 10% have been identified in previous genetic screens. We use the data obtained from the RNAi tests to build gene clusters based on a phenotypic analysis. The clusters are then used to guide two broad lines of investigation: (1) functional analysis of the genome, and (2) molecular dissection of specific cellular processes.

From the initial clustering studies, we have found groups of genes required for basic processes such as nuclear movements, mitotic spindle formation, cytokinesis, cell cycle progression, and proper asymmetric cell division. In many cases, these clusters contain genes that are conserved in humans. However, their function in humans is not yet known. Therefore, our data can be used not only to analyze the C. elegans genome but also to guide the functional examination of the human genome. In our current dataset, we have already found genes for which the human homolog is associated with a genetic disease, including some that have been previously targeted for anti-cancer drug development.

In a related project, we are using the early nematode embryo as a model to study the evolution of developmental mechanisms. Comparisons across species have revealed fundamental differences during early embryogenesis. Significantly, in some species, the wild-type patterns of early cleavages resemble those produced by various C. elegans mutants. We are examining these phenotypic differences in conjunction with molecular analyses to identify mechanisms underlying the phenotypic diversity seen in nature.