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Single nucleotide polymorphisms in serotonin receptor 4 ( HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4<jats:sup>\u2212\/\u2212<\/jats:sup> animals. We report here that the Htr4<jats:sup>\u2212\/\u2212<\/jats:sup> phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4<jats:sup>\u2212\/\u2212<\/jats:sup> airway hyperresponsiveness phenotype. Hyperpolarized <jats:sup>3<\/jats:sup>He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4<jats:sup>\u2212\/\u2212<\/jats:sup> mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with\/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4\u2019s role in pulmonary function likely relates to neural innervation and control of breathing. <\/jats:p>","DOI":"10.1152\/ajplung.00495.2016","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T21:40:33Z","timestamp":1485553233000},"page":"L520-L530","source":"Crossref","is-referenced-by-count":2,"title":["Vagal innervation is required for pulmonary function phenotype in <i>Htr4<sup>\u2212\/\u2212<\/sup><\/i> mice"],"prefix":"10.1152","volume":"312","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8447-7871","authenticated-orcid":false,"given":"John S.","family":"House","sequence":"first","affiliation":[{"name":"Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cody E.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Immunity, Inflammation, 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