The Integrator complex desensitizes cellular response to TGFbeta/BMP signaling

The maintenance of stem cells requires the concerted actions of niche-derived signals and stem cell-intrinsic factors. Although Decapentaplegic (Dpp), a Drosophila BMP molecule, can act as a long-range morphogen, its function is spatially limited to the germline stem cell niche in the germarium. We show here that Integrator, a complex known to be involved in RNAPII-mediated transcriptional regulation in the nucleus, promotes germline differentiation by restricting niche-derived Dpp/BMP activity in the cytoplasm. Mechanistically, our results show that Integrator forms a multi-subunit complex with type I receptor Thickveins (Tkv) and other signaling components of the Dpp/BMP pathway and acts in a negative feedback loop to promote Tkv turnover, independently of its transcriptional activity. Further, we show that Integrator works in various developmental contexts to desensitize cellular response to Dpp/BMP signaling during Drosophila development. Similarly, human Integrator subunits bind TGF?/BMP signaling components and antagonize its activity, suggesting a novel conserved role of Integrator across metazoans.