Dr. James Douglas McGhee

The focus of my laboratory is understanding the molecular basis of lineage-specific gene expression. How does one particular cell know that it will produce an intestinal cell, for example, and not a muscle or a neuron? The experimental system on which we work and which we have been developing for the past dozen years is the development of the intestine in the simple nematode Caenorhabditis elegans. This is a wonderfully simple lineage because the entire intestine derives from a single cell in the 8-celled embryo. The aim is to understand what transcription factors and what transcription factor cascades operate within the developing intestine, in order to turn on the genes that encode the structural proteins and enzymes that allow the intestine to function.

Most of our work now focuses on two transcription factors that, between them, are expressed in every cell of the C. elegans embryonic digestive tract. The first factor is a GATA transcription factor called elt-2, which is expressed in every cell of the gut, beginning when the gut has two cells and persisting for the life of the worm; null mutants in elt-2 are lethal. elt-2 appears homologous to Drosophila serpent and vertebrate GATA4,5,6, other endoderm associated GATA factors. The second factor is a fork head homolog that we cloned and recently identified with a gene called pha-4, previously shown by others to be necessary for crucial early steps in pharynx and rectum organogenesis. The questions to be asked are similar for elt-2 and for pha-4: What downstream genes do they control and how do they control them? What upstream genes control elt-2 and pha-4 and how do they control them? The experimental approaches range from classical genetic screens, molecular genetic analysis of promoters and the detailed biochemistry of DNA-protein interactions, all with the aim of understanding how genes (and embryos) do what they do.

Our overall view is that knowing how individual transcription factors control individual genes will not be enough to understand gut development. Rather, it will be necessary to understand how these factors interact within a complex and redundant regulatory network. We wish to understand how the stable behaviours of such networks give rise to stable "cell fates" and how such networks respond to evolutionary pressure. The power of C. elegans as an experimental system may actually make it feasible to understand digestive tract development at a satisfying, perhaps even a quantitative level.