My lab uses molecular genetic approaches to address two questions in neurobiology. In our first project, we are interested in how different neurotransmitters affect the behavior of an organism. We are using the nematode Caenorhabditis elegans as our model system and have focused on examining the role of a specific class of neurotransmitter, the neuropeptides. We are interested in the family of FMRFamide-related peptides, which have been implicated in pain modulation in mammals. At least 31 genes encode FMRFamide-related peptides, or FLPs, in C. elegans. To understand the role of the different flp genes, we have begun the task of determining the expression pattern and knocking out each flp gene. Although there is functional overlap between the genes, inactivation of certain flp genes leads to behavioral defects, including defects in movement, reproduction, oxygen response, and fat accumulation. Insights into the role of the flp genes may reveal how neuropeptides are used in mammalian systems as well as in parasitic nematodes, which infect over one billion people worldwide.
In a second project, we are using C. elegans as a model to examine genes implicated in neurodegenerative disorders. Mutations in the human APP gene have been linked to familial Alzheimer's Disease. The functions of APP and APP-related genes in humans, however, are unclear. C. elegans contains one APP-related gene, apl-1, which encodes a protein that is highly similar to human APP. apl-1 has an essential function in C. elegans. Loss of apl-1 disrupts several developmental processes, including molting and morphogenesis, and results in larval lethality. Expression of the extracellular domain of APL-1 is sufficient to rescue the apl-1 lethality, suggesting that apl-1 acts non-cell autonomously as a signaling molecule. Overexpression of APL-1 also causes several phenotypes, including an incompletely penetrant lethality, suggesting that levels of APL-1 need to be tightly regulated to ensure the animal’s viability. We are examining the role of apl-1 and identifying the genes that act in the same pathway as apl-1. Although different organisms may use APP and related proteins in different functional contexts, the pathways in which they function and the molecules with which they interact are likely to be conserved. Hence, identification of pathways relevant to APL-1 may provide insights into the roles and cellular pathways of human APP.