biostudies-literatureGlaser JSwiss National Science FoundationDeutsche Forschungsgemeinschaft (German Research Foundation)National Centre of Competence in Research Robotics (Swiss National Center of Competence in Research "Robotics")Human Frontier Science Program (HFSP)1766-1776https://www.ebi.ac.uk/biostudies/studies/S-EPMC12283350biostudies-literatureUnknown57(7)Transposable elements (TEs) are scattered across mammalian genomes. Silencing of TEs prevents harmful effects caused by either global activation leading to genome instability or insertional mutations disturbing gene transcription. However, whether the activation of a TE can cause disease without directly affecting gene expression is largely unknown. Here we show that a TE insertion can adopt nearby regulatory activity, resulting in the production of cell-type-specific viral-like particles (VLPs) that affect embryo formation. Failure to silence an LTR retrotransposon inserted upstream of the Fgf8 gene results in their co-expression during mouse development. VLP assembly in the Fgf8-expressing cells of the developing limb triggers apoptotic cell death, resulting in a limb malformation resembNature geneticsEnhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes.PMC12283350176802PP00P3_210995-6MU 880/16-1PP00P3_176802LT000465/2019-LChan WLAndrey GAktas YBartzoka NPrada-Medina CAGlaser JWittler LSchopflin RPhan MHQLaupert VMundlos SFauler BPaliou CMielke TCova GStanislas VFranke MfalseEnhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes.Transposable elements (TEs) are scattered across mammalian genomes. Silencing of TEs prevents harmful effects caused by either global activation leading to genome instability or insertional mutations disturbing gene transcription. However, whether the activation of a TE can cause disease without directly affecting gene expression is largely unknown. Here we show that a TE insertion can adopt nearby regulatory activity, resulting in the production of cell-type-specific viral-like particles (VLPs) that affect embryo formation. Failure to silence an LTR retrotransposon inserted upstream of the Fgf8 gene results in their co-expression during mouse development. VLP assembly in the Fgf8-expressing cells of the developing limb triggers apoptotic cell death, resulting in a limb malformation resemb2025-01-01T00:00:00Z2025 Jul2026-03-17T15:18:08.776Z2025-08-16T03:06:12.91ZS-EPMC122833504063470610.1038/s41588-025-02248-5