Genetic Analysis of Germ Cell Immortality



 DESCRIPTION (provided by applicant): Germ cells maintain themselves in a pristine condition that allows for indefinite proliferation as they are passed from one generation to the next. In contrast, somatic cells, including somatic stem cells, are only needed for a single generation and may 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. We discovered that the C. elegans Piwi homolog prg-1 promotes germ cell immortality via small RNA-mediated silencing of the epigenome and that the transgenerational fertility defect of Piwi/piRNA mutants can be suppressed by activation of a major somatic longevity pathway. We propose 1) to study how the insulin/IGF-1 signaling pathway suppresses the transgenerational fertility defect of Piwi mutants, 2) to study the sterilit phenotype of Piwi mutants, which may represent a state of suspended animation, and 3) to more thoroughly explore how the transgenerational sterility phenotype of Piwi mutants can be suppressed. The proposed experiments should provide insight into 1) a form of heritable epigenetic stress that can be transmitted by germ cells and 2) the organismal response to high levels of this stress. We could uncover fundamental principles relevant to transgenerational regulation of aging.