Conserved innate immunity components limit transgene expression in adult planarians

Drees, Leonard, Blösel, Daniel, Kowalewski, Johannes, Weill, Uri and Rink, Jochen (2026) Conserved innate immunity components limit transgene expression in adult planarians. Development, 153 (205222).

Abstract

The planarian flatworm Schmidtea mediterranea has become a powerful model for studying whole-body regeneration, tissue patterning, and stem cell regulation. Yet the absence of reliable tools for transgene expression still limits the elucidation of molecular mechanisms in in this system. Here, we establish a proof-of-principle system for plasmid-based expression of NanoLuciferase (NanoLuc) in S. mediterranea, employing commercially available transfection reagents and a panel of endogenous promoter sequences. Despite successful delivery, reporter expression remained low and transient. To identify biological barriers to robust transgene expression, we investigated the role of innate immune pathways. Candidate gene searches and biochemical pull-down of cytoplasmic DNA coupled to mass spectrometry identified several planarian homologs of conserved immune regulators and putative DNA sensors. Through RNAinterferencescreeningofconservedinnateimmunecomponents, weuncoverrolesforS.mediterraneahomologsofTank-bindingkinase 1 (TBK1) and macrophage mannose receptor 1 (MRC1) as potent repressors of transgene expression. Transcriptomic and functional analyses further implicate TBK1 in regulating broad innate immune and stress-response programs, akin to its vertebrate function. Together, our findings demonstrate that innate immune signaling limits transgene expression in S. mediterranea and suggest that modulating these pathways maybekeytoenablingstableandefficient genetic manipulation in planarians.

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