Endogenous retroviruses in development and health

Endogenous retroviruses (ERVs) are evolutionary remnants of retroviral infections in which the viral genome became embedded as a dormant regulatory element within the host germline. When ERVs become activated, they comprehensively rewire genomic regulatory networks of the host and facilitate critical developmental events, such as preimplantation development and placentation, in a manner specific to species, developmental stage, and tissues. However, accumulating evidence suggests that aberrant ERV transcription compromises genome stability and has been implicated in cellular senescence and various pathogenic processes, underscoring the significance of host genomic surveillance mechanisms. Here, we revisit the prominent functions of ERVs in early development and highlight their emerging roles in mammalian post-implantation development and organogenesis. We also discuss their implications for aging and pathological processes such as microbial infection, immune response. Furthermore, we discuss recent advances in stem-cell-based models, single-cell omics, and genome editing technologies, which serve as beacons illuminating the versatile nature of ERVs in mammalian development and health.