Germ cells are designed to maintain an effectively unlimited proliferative capacity in order to fulfill their biological purpose: to be passed from one generation to the next, indefinitely. In contrast, somatic cells, including somatic stem cells, are only needed for a single generation. Somatic cells may therefore be deficient for mechanisms that ensure an unlimited proliferative capacity. This dichotomy between germ and soma cells may be the ultimate cause of human proliferative aging and may contribute to some age-related diseases such as tumorigenesis. The long-term goal of this project is to study the mechanisms by which germ cells maintain an unlimited proliferative capacity. Many C. elegans mortal germline mutants that are compromised for germ cell immortality have been isolated. A limited number of mortal germline mutants will be mapped genetically and cloned. The phenotypes of these mortal germline mutants will be characterized, and mechanisms that promote germ cell immortality will be investigated. Pathway analysis will be conducted by constructing double mutants, which ought to reveal how different forms of proliferative damage interact in vivo. The relationship between proliferative and post-mitotic aging will be studied for some C. elegans mortal germline mutants. This project utilizes forward genetics to study the molecular basis of the proliferative immortality of germ cells in whole animals. This project will define a number of genes and several pathways, aside from telomerase, that repress proliferative aging in germ cells. Some of these genes or pathways may be deficient in mammalian somatic cells and may therefore affect how we age.
|Heestand, Bree; Simon, Matt; Frenk, Stephen et al. (2018) Transgenerational Sterility of Piwi Mutants Represents a Dynamic Form of Adult Reproductive Diapause. Cell Rep 23:156-171|
|Frenk, Stephen; Houseley, Jonathan (2018) Gene expression hallmarks of cellular ageing. Biogerontology 19:547-566|
|Leopold, Luciana E; Heestand, Bree N; Seong, Soobin et al. (2015) Lack of pairing during meiosis triggers multigenerational transgene silencing in Caenorhabditis elegans. Proc Natl Acad Sci U S A 112:E2667-76|
|Alvares, Stacy M; Mayberry, Gaea A; Joyner, Ebony Y et al. (2014) H3K4 demethylase activities repress proliferative and postmitotic aging. Aging Cell 13:245-53|
|Sakaguchi, Aisa; Sarkies, Peter; Simon, Matt et al. (2014) Caenorhabditis elegans RSD-2 and RSD-6 promote germ cell immortality by maintaining small interfering RNA populations. Proc Natl Acad Sci U S A 111:E4323-31|
|Simon, Matt; Sarkies, Peter; Ikegami, Kohta et al. (2014) Reduced insulin/IGF-1 signaling restores germ cell immortality to Caenorhabditis elegans Piwi mutants. Cell Rep 7:762-73|
|Ashe, Alyson; Sapetschnig, Alexandra; Weick, Eva-Maria et al. (2012) piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150:88-99|