Physiological responses to early life stress during development and adulthood in Caenorhabditis elegans

Abstract

Adult metabolic disease and cancer are multifaceted and regulated by a host of diverse causes which can be immediate or long-term. The medical concept of the Developmental Origins of Health and Disease (DOHaD) has been established to characterize and investigate how conditions during gestation and development can predispose or directly cause diseases later in life. These can include modifications to the epigenome and changes in metabolic signaling. Research in mammals and human cohorts is limited by the availability of viable case-studies, complex ethical and social influences, and challenges associated with tracking individuals with dynamic and longitudinal development. Therefore, establishing a viable model system to investigate the interaction between physiology, genetics, and the environment is pivotal to understanding the developmental origins of adult disease.Here, we implement the nematode Caenorhabditis elegans to study how extended starvation and developmental arrest affects the formation of developmental abnormalities and tumors in the reproductive system. We leverage the ability of C. elegans to arrest growth after hatching in response to the absence of food as a model for adverse developmental conditions. It has been previously demonstrated that extended early larval arrest increases the incidence of tumors in recovered adults, however the full scope of their regulation and proximal causes is not known.We show that insulin-like/insulin-like growth factor signaling (IIS), a critical regulator of starvation resistance and recovery, is subject to dynamic regulation via ubiquitination. Specific ubiquitination sites and ubiquitin ligase genes function in a context-dependent manner, altering phenotypes at different life stages and environmental conditions. We also show that starvation-induced gonad abnormalities are regulated independently of IIS and its downstream effectors via IIS-independent activity of DAF-18/PTEN through the pocket protein LIN-35/Rb. We implicate C. elegans Hh-related signaling downstream of lin-35 and demonstrate that genes in this pathway transcriptionally regulate components of the innate immune system following extended larval arrest. These innate immunity genes are crucial to the regulation of starvation-inducedabnormalities and pathogen resistance. We also extend our previous analysis of the Wnt and lipid synthesis pathways, previously shown to act downstream of IIS to regulate the formation of gonad abnormalities and characterize their genetic interactions with Hh-related signaling. Additionally, we investigate the role of the C. elegans TOR pathway in the regulation of starvation-induced abnormalities and characterize its interactions with other relevant pathways. Overall, we expand previous work analyzing the regulation of complex developmental phenotypes following early-life stress and show that a potential fitness trade-off may exist in the induction of innate immunity and pathogen resistance at the cost of reduced developmental fidelity.