Cross-Species Roles of TCER-1/TCERG1 in Fertility and Reproductive Aging

About This Grant

ABSTRACT Across species, reproduction and immunity compete for limited physiological resources—a trade-off that becomes increasingly consequential with age, as both reproductive capacity and immune competence decline. In mammals, proteins that mediate these relationships to coordinate reproductive investment, immune regulation, and somatic maintenance are scarcely defined. This presents a critical gap in our understanding of reproductive aging and age-related disease susceptibility. This proposal investigates whether the C. elegans protein TCER-1, an established regulator of the fertility–immunity–longevity axis, has a conserved functional homolog in mammals. We previously identified TCER-1 as a pro-longevity factor that maintains fertility with age by suppressing immune and stress responses. Its homolog in Arabidopsis also promotes fertility and represses immunity, and our collaborative studies reveal a similar role for the Drosophila TCER-1 in repressing stress resistance, highlighting conserved trade-off regulation across kingdoms. TCER-1 is homologous to the mammalian transcription elongation and splicing factor, TCERG1, which has been linked to human disease in GWAS studies, though it’s in vivo function remains uncharacterized. This proposal is based on our preliminary data showing that (i) worm and mammalian TCERG1 both regulate alternative splicing of immune-related genes, and importantly (ii) mouse and human TCERG1 are enriched in germ-cells and exhibit a major age-related decline in female oocytes. In this exploratory proposal, we aim to assess whether human or mouse TCERG1 can functionally replace TCER-1 in C. elegans (Aim 1) and to define the role of mouse TCERG1 in fertility, ovarian reserve and reproductive aging by using existing and newly generated knockout models (Aim 2). By uncovering a potentially conserved molecular regulator of physiological trade-offs, this project aims to illuminate how reproductive aging shapes immune function and broader somatic aging, and to lay the groundwork for future interventions that support reproductive health in aging individuals.