EMX2-GPR156-Gαi reverses hair cell orientation in mechanosensory epithelia

Hair cells detect sound, head position or water movements when their mechanosensory hair bundle is deflected. Each hair bundle has an asymmetric architecture that restricts stimulus detection to a single axis. Coordinated hair cell orientations within sensory epithelia further tune stimulus detection at the organ level. Here, we identify GPR156, an orphan GPCR of unknown function, as a critical regulator of hair cell orientation. We demonstrate that the transcription factor EMX2 polarizes GPR156 distribution, enabling it to signal through G alpha i and trigger a 180 degrees reversal in hair cell orientation. GPR156-G alpha i mediated reversal is essential to establish hair cells with mirror-image orientations in mouse otolith organs in the vestibular system and in zebrafish lateral line. Remarkably, GPR156-G alpha i also instructs hair cell reversal in the auditory epithelium, despite a lack of mirror-image organization. Overall, our work demonstrates that conserved GPR156-G alpha i signaling is integral to the framework that builds directional responses into mechanosensory epithelia. Sensory hair cells develop an asymmetric architecture to restrict stimulus detection to a single axis. Here the authors identify GPR156 as directing a 180-degree reversal in hair cell orientation through G alpha i, downstream of EMX2 in the mouse inner ear and zebrafish lateral line.