Frey, A.; Ernst, L.; Fischer, F.; Alpar, L.; Bellaiche, Y.; Classen, A.-K.

Tissue-intrinsic surveillance systems play an important role in maintaining tissue health by detecting and eliminating aberrant cells. One such system, interface surveillance, is activated by differences in cell fate programs between neighboring cells. Activation of interface surveillance drives separation and elimination of aberrant cells by recruitment of actin regulators and Myosin II to neighboring cell contacts, as well as activation of JNK signaling and apoptosis at this interface. Here, we uncover the role of long Toll receptors (Toll-2, Toll-6, Toll-7, Toll-8) as key mediators of interface surveillance in Drosophila wing imaginal discs. Using genetic mosaics combined with spatial mapping of Toll receptor expression patterns, we demonstrate that differences in long Toll receptor expression levels between neighboring cells trigger all hallmark responses of interface surveillance. This response is position-dependent and relies on the comparison of expression levels established by cell-fate-specifying programs. Specifically, we show that the expression of long Toll receptors is regulated by multiple fate-patterning pathways, giving rise to a combinatorial cell surface code that is deregulated in developmentally aberrant or oncogenic cells. Remarkably, Toll receptor-mediated surveillance operates independently of canonical NF-kB signaling, and rather mirrors a distinct role of long Toll receptors in modulating cell-cell affinity via actomyosin dynamics during early embryogenesis. Our findings identify long Toll receptors as integrators of developmental patterning and tissue homeostasis mechanisms and provide insights into how tissues detect and respond to potentially oncogenic mutations that misregulate cell fate specification pathways.