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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\u03b1i and trigger a 180\u00b0 reversal in hair cell orientation. GPR156-G\u03b1i 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\u03b1i also instructs hair cell reversal in the auditory epithelium, despite a lack of mirror-image organization. Overall, our work demonstrates that conserved GPR156-G\u03b1i signaling is integral to the framework that builds directional responses into mechanosensory epithelia.<\/jats:p>","DOI":"10.1038\/s41467-021-22997-1","type":"journal-article","created":{"date-parts":[[2021,5,17]],"date-time":"2021-05-17T10:04:53Z","timestamp":1621245893000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["EMX2-GPR156-G\u03b1i reverses hair cell orientation in mechanosensory epithelia"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1065-8215","authenticated-orcid":false,"given":"Katie S.","family":"Kindt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Akturk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9519-3559","authenticated-orcid":false,"given":"Amandine","family":"Jarysta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0422-2132","authenticated-orcid":false,"given":"Matthew","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alisha","family":"Beirl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Flonard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2708-6273","authenticated-orcid":false,"given":"Basile","family":"Tarchini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,17]]},"reference":[{"key":"22997_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cell.2009.09.010","volume":"139","author":"PG Gillespie","year":"2009","unstructured":"Gillespie, P. 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