Our research addresses two major areas organismal aging and the biology of metals during growth and development.
Our studies of metals focus on zinc, which is essential for all life. To investigate zinc biology, we combine genetic analysis of C. elegans with biochemical analysis of purified proteins. Because zinc homeostasis pathways have been extensively conserved, we can translate discoveries made in worms into mammalian systems. We have identified a family of zinc transport proteins (CDF) that mediate high zinc homeostasis by sequestering zinc in lysosomes or excreting zinc out of the animal. These transporters are regulated by a zinc sensing transcription factor in the nuclear receptor family that we recently identified in a genetic screen. Low zinc homeostasis is mediated by a second family of transporters (ZIP) that import zinc into the cytoplasm. We are characterizing the transcriptional control of these transporters by low zinc. We discovered that one ZIP transporter mediates zinc signaling during sperm activation. We hope to understand how animals sense both high and low zinc and maintain homeostasis, and how zinc is used as a second messenger to transmit information during sperm activation.
The progressive, degenerative changes that occur as animals age are of fundamental importance, yet poorly understood. C. elegans is well suited for investigating aging, since it has a short life span of ~18 days. We have characterized phenotypic changes that occur as worms age, and we have identified a class of anticonvulsant drugs and a hypertension medicine that delay age-related degeneration. We hope to define regulatory circuits that control aging and develop therapies that delay aging.
Here are a few of our ongoing and recently published projects. In addition to these, there are ongoing projects about cadmium toxicity, sperm activation, and population dynamics. Contact us to learn more about these!
Mechanisms that control aging are important yet poorly defined. To discover longevity control genes, we performed a forward genetic screen for delayed reproductive aging in C. elegans. Here, we show that am117 is a nonsense mutation in the phm-2 gene, which encodes a protein homologous to human scaffold attachment factor B. phm-2(lf) mutant worms have an abnormal pharynx grinder, which allows live bacteria to accumulate in the intestine. This defect shortens lifespan on highly pathogenic bacteria but extends lifespan and health span on the standard E. coli diet by activating innate immunity pathways that lead to bacterial avoidance behavior and dietary restriction. eat-2(lf) mutants displayed a similar phenotype, indicating accumulation of live bacteria also triggers extended longevity in this mutant. The analysis of phm-2 elucidates connections between pathogen response and aging by defining a mechanism of longevity extension in C. elegans—bacterial colonization, innate immune activation, and bacterial avoidance behavior.
Read more in Sandeep’s 2019 Developmental Cell paper.
C. elegans hermaphrodites display dramatic age-related decline of reproduction early in life, while somatic functions are still robust. To understand reproductive aging, we analyzed the assembly line of oocyte production that generates fertilized eggs. Aging germlines displayed both sporadic and population-wide changes. A small fraction of aging animals displayed endomitotic oocytes in the germline and other defects. By contrast, all animals displayed age-related decreases in germline size and function. As early as day 3 of adulthood, animals displayed fewer stem cells and a slower cell cycle, which combine to substantially decrease progenitor zone output. The C. elegans germline is the only adult tissue that contains stem cells, allowing the analysis of stem cells in aging. To investigate the mechanism of the decrease in stem cell number, we analyzed the Notch signaling pathway. The Notch effectors LST-1 and SYGL-1 displayed age-related decreases in expression domains, suggesting a role for Notch signaling in germline aging. The results indicate that although sporadic defects account for the sterility of some animals, population-wide changes account for the overall pattern of reproductive aging.
Read more in Zuzana’s 2019 Development paper.
Zinc is an essential nutrient for all life forms, and maintaining zinc homeostasis is critical for survival. However, little is known about how animals sense changes in zinc availability and make adjustments to maintain homeostasis. In particular, logic dictates there must be a mechanism for zinc sensing, but it has not been defined in animals. We discovered that the nuclear receptor transcription factor HIZR-1 is the master regulator of high zinc homeostasis in the roundworm Caenorhabditis elegans. In response to high dietary zinc, HIZR-1 activates transcription of multiple genes that encode a network of proteins that store and detoxify excess zinc. Furthermore, our results suggest HIZR-1 itself is the high zinc sensor, since it directly binds zinc ions in the ligand-binding domain that regulates transcriptional activation. These findings advance the understanding of zinc homeostasis and nuclear receptor biology. Nuclear receptors were initially characterized as receptors for hormones such as estrogen, indicating complex animals use these transcription factors to monitor their internal environment. However, nuclear receptors are present in simple organisms that lack endocrine signaling, suggesting these transcription factors might have a primordial function in sensing the external environment. Our results identify a new class of nuclear receptor ligands, the inorganic ion zinc, and a new function for nuclear receptors in directly sensing levels of a nutrient. We speculate that nutrient homeostasis mediated by direct binding of nutrients to the ligand-binding domain is a primordial function of nuclear receptors, whereas endocrine signaling in complex animals mediated by direct binding of hormones to the ligand-binding domain is a derived function of nuclear receptors that appeared later in evolution.
Read more in Kurt’s 2017 PLOS Biology paper.
Sperm are specialized cells with transcriptionally silent DNA that has been packaged for delivery into the egg. In their final step of development, immature sperm undergo a rapid transition from nonmotile cells to mature, motile sperm capable of fertilization. The signals that trigger this change are not clearly understood. By identifying mutants in the roundworm Caenorhabditis elegans that are defective in sperm activation, we discovered a conserved transmembrane protein, ZIPT-7.1, that transports zinc and promotes sperm activation in both sexes. ZIPT-7.1 is expressed in the germ line and functions there to control sperm activation. When expressed ectopically in mammalian cells, the protein specifically transports zinc across membranes and localizes primarily to membranes within the cell. Previous genetic studies had identified two pathways that mediate sperm activation in C. elegans, and our results suggest that zipt-7.1 acts at the end of one of these two, the spe-8 pathway. We propose that when this pathway triggers sperm activation, it acts through ZIPT-7.1, which mediates the release of zinc from internal stores in the immature sperm. This released zinc functions as a second messenger to promote the differentiation of mature, motile sperm.
Read more in James’s 2018 PLOS Biology paper.