{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:01:16Z","timestamp":1785427276132,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,5]]},"group-title":"Neuroscience","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T00:00:00Z","timestamp":1783209600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R01 EY032095"],"award-info":[{"award-number":["R01 EY032095"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RBP Stein Innovation Award"],"award-info":[{"award-number":["RBP Stein Innovation Award"]}],"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The optokinetic reflex (OKR) is an evolutionarily conserved reflexive behavior that ensures image stabilization on the retina during global motion. It consists of smooth eye tracking movements in the direction of the moving stimulus interspersed with rapid resetting saccades. This reflex is driven by retinal ON direction-selective ganglion cells (oDSGCs), which comprise distinct subtypes tuned either to vertical or horizontal motion. oDSGCs convey directional signals to the brain via precise axonal projections to specific accessory optic system (AOS) nuclei. However, the mechanisms that establish and maintain the specificity of these circuits remain poorly understood. Here, we identify a critical role for the mechanosensitive ion channel Piezo2 in refining AOS circuitry to ensure appropriate eye movement responses. Single-cell transcriptomic profiling revealed selective enrichment of Piezo2 in horizontally-tuned oDSGCs. We show that both loss and hyperactivation of Piezo2 in retinal neurons leads to cross-coupling of horizontal and vertical OKR responses, producing aberrant diagonal eye tracking movements during horizontal optokinetic stimulation. Mechanistically, Piezo2 regulates the developmental refinement of oDSGC axonal projections within the AOS, and disruption of this process results in persistent ectopic innervation that enables aberrant crosstalk between horizontal and vertical motion pathways. These findings reveal a channel activity-dependent mechanism that ensures the functional segregation of directional motion circuits underlying gaze stabilization.<\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        <jats:italic>Piezo2<\/jats:italic>\n                        is selectively expressed in forward-tuned ON and ON-OFF DSGCs that innervate the accessory optic system\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Both loss and overactivation of Piezo2 induce cross-coupling of horizontal and vertical optokinetic reflexes<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Piezo2 function in ON-OFF DSGCs is dispensable for normal optokinetic reflex responses<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Retinal Piezo2 refines axonal targeting to the accessory optic system nuclei, ensuring proper optokinetic reflex function<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.30.735567","type":"posted-content","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T03:30:14Z","timestamp":1783308614000},"source":"Crossref","is-referenced-by-count":0,"title":["The mechanotransduction channel Piezo2 refines axonal projections to the accessory optic system and regulates the optokinetic reflex"],"prefix":"10.64898","author":[{"given":"Natalie R.","family":"Hamilton","sequence":"first","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria N.","family":"Neckles","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timour","family":"Al-Khindi","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitya","family":"Donthi","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Mizutori","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Fu","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K.","family":"Kiraly","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bea C.","family":"Winship","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7562-5513","authenticated-orcid":false,"given":"Alex L.","family":"Kolodkin","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3533-3027","authenticated-orcid":false,"given":"Karina","family":"Chaudhari","sequence":"additional","affiliation":[{"name":"Solomon H. 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