Dr. Eric J. Aamodt's Research Focus

Research interests

Our lab uses the elegant and well-studied model C. elegans to study transcriptional regulation of gene expression during development. Recent studies of C. elegans and other simple animal model systems have identified regulatory genes that encode molecules that determine when and where other genes, including other regulatory genes, are expressed. Early gene expression patterns determine when and where other regulatory genes are expressed as well as the basic morphology of the animal. In these simple model organisms, and probably in all animals, numerous developmental regulators are expressed in patterns that overlap in time and space. These regulatory molecules interact to activate new regulatory genes that specify cell type and demarcate regions, such as organs, for specialization. We are following two lines of inquiry: First, we are studying how the transcription factor PAG-3 regulates neuronal specification and cell lineage. Second, we are studying the role of the cytoskeleton protein PTL-1 in neurogenesis.

1. The C. elegans pag-3 gene encodes a C2H2 zinc finger transcription factor, PAG-3, which is involved in neuronal specification and cell lineage regulation. PAG-3 is 78% identical to the human proto-oncoprotein Gfi-1 over its five zinc fingers and 88% identical to the Drosophila neurogenesis protein senseless (also known as Lyra) over the four zinc fingers of senseless. Gfi-1 is a mammalian cellular proto-oncogene identified as a target for provirus integration in retrovirus-induced T-cell-lymphomas (Gilks et al., 1993; Scheijen et al., 1997; Schmidt et al., 1996). Gfi-1B, another mammalian proto-oncogene, inhibits myeloid cell differentiation. Both Gfi-1 and Gfi-1B are transcriptional repressors (Grimes et al., 1996). Senseless is a C2H2 zinc finger transcription factor that is central to the proneural signaling pathway in Drosophila. In pag-3 mutants, the BDU interneurons adopt the fate of their lineal sisters, the ALM touch neurons (Jia et al., 1996; Jia et al., 1997); the Pn.aaa neuroblasts often reiterate the fate of their mothers the Pn.aa cells, which results in extra Pn.aap like cells (Cameron et al., 2002); and descendants of the P neuroectoblast cells that would normally undergo programmed cell death, often fail to die (Cameron et al., 2002). We are analyzing the pag-3 transcriptional pathways and relating these to Gfi-1 and senseless pathways.

2. A second project in the lab is aimed at understanding the role of the cytoskeleton in C. elegans development. We have focused on a gene we call ptl-1, which encodes a protein homologous to the microtubule-associated protein tau. The tau proteins are found exclusively in axons and are the major component of the paired helical filaments present in the brains of Alzheimer's disease patients. C. elegans provides a useful system to study the role of this and other cytoskeletal proteins in vivo. Deletion of ptl-1 does not cause a phenotype but we have identified ptl-1 synthetic lethal mutations. We are currently characterizing these mutations and cloning the genes identified by these mutations.

Caenorhabditis elegans

C. elegans, a small free-living nematode, is the simplest and best characterized multicellular model system complex enough to have tissues, organs, a true nervous system and behavior. C. elegans is an ideal system for this study. The life cycle of this simple animal requires only 2.5 days at 25oC (Wood, 1988). C. elegans normally reproduces as a self-fertilizing hermaphrodite (XX), but males, generated by nondisjunction of the X-chromosome (XO), can be maintained in culture by genetic crosses. Because C. elegans is transparent, every nucleus can be followed at every stage of development with DIC microscopy and green fluorescent protein (GFP) signals can be followed by fluorescence microscopy. Among the monumental achievements in the analysis of this animal, four stand out. The complete cell lineage from fertilized oocyte to adult is known (Sulston and Horvitz, 1977; Sulston et al., 1983). The complete wiring diagram of the nervous system is known (White et al., 1986). A physical map consisting of C. elegans genomic DNA cloned into overlapping cosmids and YACs has been made (Coulson, 1991; Coulson et al., 1986; Coulson et al., 1988), and the entire genome has been sequenced (TheC.elegansSequencingConsortium., 1998).

C. elegans is a powerful genetic system. Mutations in thousands of genes have been identified and positioned on a detailed genetic map. The physical map and the genetic map have been correlated, which aids the cloning of genes by transformation rescue. C. elegans can be easily transformed (Fire, 1986; Mello et al., 1991) and genes can be easily knocked out by injecting double-stranded RNA (RNAi) (Fire et al., 1998). Projects to generate deletions in every predicted gene in C. elegans (http://ko.cigenomics.bc.ca/elegans/), identify expression patterns for many C. elegans genes (http://watson.genes.nig.ac.jp/db/, http://www.personal.leeds.ac.uk/~acedb/Hope/epa.htm), and identify every C. elegans protein-protein interaction by massive yeast 2-hybrid screening (Walhout et al., 2000) are in progress.