Glia-derived exosomal miR-274 targets Sprouty in trachea and synaptic boutons to modulate growth and responses to hypoxia

Abstract

Secreted exosomal miRNAs mediate inter-organ/tissue communication by downregulating gene expression, thereby modulating developmental and physiological functions. However, the source, route, and function have not been formally established for specific miRNAs. Here, we show that glial miR-274 non-cell autonomously modulates the growth of synaptic boutons and tracheal branches. Whereas precursor miR-274 was expressed in glia, mature miR-274 was secreted. miR-274 secretion to circulating hemolymph was detected in exosomes, a process requiring ESCRT components in exosome biogenesis and Rab11 and Syx1A in exosome release. miR-274 downregulated Sprouty to activate MAPK in synaptic boutons and tracheal branches, thereby promoting their growth. Expression of miR-274 solely in glia of a mir-274 null mutant reset normal levels of Sprouty and MAPK, and hemolymphatic exosomal miR-274. mir-274 mutant larvae were hypersensitive to hypoxia, which was suppressed by increasing tracheal branches. Thus, glia-derived miR-274 coordinates growth of synaptic boutons and tracheal branches to modulate larval hypoxia responses.