Joel H. Rothman
During the developmental progression of a single egg cell into a complex multicellular animal, how do cells learn what to become at the proper time and location? We are using genetic, embryological, and molecular methods to study the control of embryonic development in the nematode Caenorhabditis elegans. The history and destiny of every cell in this organism is know, making it possible to analyze the action of developmentally important molecules at the resolution of single identified cells. Our primary approach is to identify genes based on their requirement in particular developmental processes and to characterize their functions molecularly.
We have isolated a large collection of mutations in genes essential for embryonic development. The development of selected mutants is followed at single-cell resolutin to provided a precise description of their developmental alterations. Molecular clones of selected genes are isolated and analysis of the sequence, patterns of expression, and biochemical nature of their products allow us to assess their action in development.
In one area, we are investigating how the innermost germ layer, or endoderm, is molecularly specified. We have identified a gene, end-1, that controls endoderm-specific differentiation. When the activity of this gene is reduced, the single endoderm progenitor no longer gives rise to endoderm, but is instead transformed to a mesodermal or an ectodermal progenitor. The end-1 gene encodes a transcription factor that regulates endoderm-specific development. This, and other gense affecting endoderm development, are being further characterized to elucidate their molecular mechanisms of action.
We are also studying how precursor cells in the early embryo decide between two fundamental cell fates: neuronal and epidermal. We have found that a simple pattern underlies this binary decision, which is controlled by short-range communication between neighboring cells. Genetic and molecular approaches are being used to identify the components that regulate this decision and other aspects of epidermal and neuronal development.
Another developmental decision that all cells must make is whether to live or die. Programmed cell death (PCD) is a genetically controlled process that eliminates extraneous or potentially harmful cells during development of most animals. Its improper regulation in humans can lead to cancer, neurodegenerative disease, and other pathologies. In C. elegans, about 10% of all cells generated are programmed to die at precisely deifned stages and positions. We are studying genes that regulate PCD. One such gene, dad-1, encodes a highly conserved protein that represses PCD, thus protecting cells from dying. We have found that the nematode and human dad-1 genes are functionally interchangeable and are currently investigating the mechanisms by which dad-1 prevents cells from undergoing PCD. We have also identified and are characterizing several new genomic regions required for the normal regulation of PCD.