repx-1 Regulates Reproductive Aging in Caenorhabditis elegans

Abstract

As more women choose to start families at later ages, age-associated infertility becomes increasingly relevant. While little is known about the genes that control reproductive aging, the model organism Caenorhabditis elegans provides an excellent platform to study this problem. Previous work in The Murphy Lab identified the receptor tyrosine kinase repx-1 as a regulator of reproductive span. This thesis strives to understand the mechanism through which loss of repx-1 extends reproductive span. We report that repx-1 loss extends reproductive span via oocyte quality maintenance. repx-1 does not extend lifespan but does alter developmental timing. Transcriptional changes in repx-1 mutants closely resemble those of crh-1 (CREB homolog) mutants, which also experience extended reproductive span but not lifespan. Many of the genes overexpressed in repx-1 mutants are implicated in fat metabolism, including a subset that is enriched for the HLH-30 (Helix-Loop-Helix 30, the C. elegans ortholog of mammalian Transcription Factor EB) binding motif. Loss or knockdown of hlh-30 further extends reproductive span in reproductive longevity mutants repx-1 and daf-2. Our results characterize repx-1 as a regulator of reproductive longevity and implicate hlh-30 in reproduction. Future work should decipher the genetic relationship between repx-1 and crh-1 through epistasis analysis. Additionally, future work should investigate how hlh-30 knockdown extends reproductive span via changes to lipid metabolism.