{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:17:59Z","timestamp":1790727479544,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The parasympathetic nervous system is critically involved in the regulation of tear secretion by activating muscarinic acetylcholine receptors. Hence, various animal models targeting parasympathetic signaling have been developed to induce dry eye disease (DED). However, the muscarinic receptor subtype (M1\u2013M5) mediating tear secretion remains to be determined. This study was conducted to test the hypothesis that the M3 receptor subtype regulates tear secretion and to evaluate the ocular surface phenotype of mice with targeted disruption of the M3 receptor (M3R\u2212\/\u2212). The experimental techniques included quantification of tear production, fluorescein staining of the ocular surface, environmental scanning electron microscopy, assessment of proliferating cells in the corneal epithelium and of goblet cells in the conjunctiva, quantification of mRNA for inflammatory cytokines and prooxidant redox enzymes and quantification of reactive oxygen species. Tear volume was reduced in M3R\u2212\/\u2212 mice compared to age-matched controls at the age of 3 months and 15 months, respectively. This was associated with mild corneal epitheliopathy in the 15-month-old but not in the 3-month-old M3R\u2212\/\u2212 mice. M3R\u2212\/\u2212 mice at the age of 15 months also displayed changes in corneal epithelial cell texture, reduced conjunctival goblet cell density, oxidative stress and elevated mRNA expression levels for inflammatory cytokines and prooxidant redox enzymes. The findings suggest that the M3 receptor plays a pivotal role in tear production and its absence leads to ocular surface changes typical for DED at advanced age.<\/jats:p>","DOI":"10.3390\/ijms22116133","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T13:25:43Z","timestamp":1623072343000},"page":"6133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Aged Mice Devoid of the M3 Muscarinic Acetylcholine Receptor Develop Mild Dry Eye Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Aytan","family":"Musayeva","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"},{"name":"Laboratory of Corneal Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7524-2117","authenticated-orcid":false,"given":"Panagiotis","family":"Chronopoulos","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8223-3689","authenticated-orcid":false,"given":"Werner E.G.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center, Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9996-2477","authenticated-orcid":false,"given":"Maximilian","family":"Ackermann","sequence":"additional","affiliation":[{"name":"Institute of Functional and Clinical Anatomy, University Medical Center, Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5553-1752","authenticated-orcid":false,"given":"Ning","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3458-7391","authenticated-orcid":false,"given":"Huige","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3506-8465","authenticated-orcid":false,"given":"Adrian","family":"Gericke","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1016\/j.ophtha.2017.07.010","article-title":"The Pathophysiology of Dry Eye Disease: 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