{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T07:13:17Z","timestamp":1774509197541,"version":"3.50.1"},"posted":{"date-parts":[[2025,11,19]]},"group-title":"Neuroscience","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD097331"],"award-info":[{"award-number":["R01HD097331"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","award":["R01HD114827"],"award-info":[{"award-number":["R01HD114827"]}]},{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"crossref","award":["R01DC017149"],"award-info":[{"award-number":["R01DC017149"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The vomeronasal organ (VNO) is a specialized chemosensory structure in the nasal cavity that detects pheromones and mediates social and reproductive behaviors. The VNO of rodents is populated by different types of vomeronasal sensory neurons (VSNs). Apical VSNs, located near the lumen, express the transcription factor (TF) Meis2, V1R family receptors, and the G protein subunit Gao; the VSNs distributed closer to the basal lamina express the TF Tfap2e\/AP-2\u03b5, V2R receptors, and the G protein subunit Gai2. In addition, sparse cells in the VNO express the Formyl Peptide Receptors (FPRs). Single-cell mRNA sequencing (scRNA Seq) identified over 980 differentially expressed genes between these cell types, with many linked to the endoplasmic reticulum (ER). Among these ER proteins, Canopy1 (Cnpy1), was found to be among the most enriched genes in V2R+ VSNs. Previously studied only in zebrafish, Cnpy1 was found to affect Fgfr1 signaling and is thus also known as \u201cFGF signaling regulator-1\u201d. In a previous study, we discovered that AP-2e upregulates Cnpy1 expression. Although Cnpy1 knockout mice are viable and have normal VNO development at birth, they experience a progressive degeneration and loss of V2R-expressing VSNs. Prior to symptoms, the basal VSNs of KO mice display reduced V2R protein immunoreactivity in the soma and a complete absence of the protein at the lumen of the VNO, rendering the neurons non-functional. Cnpy1 KOs exhibit altered guidance cues and adhesion molecule expression, along with disrupted connectivity to the accessory olfactory bulb (AOB). Our study shows that distinct neuronal types depend on unique ER protein repertoires to maintain proper proteostasis. The loss of Cnpy1 highlights the importance of cell\u2013type\u2013specific ER factors in the differentiation and function of specific neurons, revealing mechanisms that drive neuronal diversity and vulnerability to ER gene disruption.<\/jats:p>","DOI":"10.1101\/2025.11.19.689260","type":"posted-content","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T05:55:18Z","timestamp":1763618118000},"source":"Crossref","is-referenced-by-count":1,"title":["Canopy1\/Cnpy1 is required for proper V2R processing and transport; its loss impairs the function and circuit organization of basal\/V2R vomeronasal sensory neurons"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8655-5469","authenticated-orcid":false,"given":"Nicholas","family":"Mathias","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8500-9079","authenticated-orcid":false,"given":"Nikki","family":"Dolphin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3771-4138","authenticated-orcid":false,"given":"Anthony","family":"Ruquet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6547-3464","authenticated-orcid":false,"given":"Paolo E","family":"Forni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025112110401434000_2025.11.19.689260v1.1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2014.00134"},{"key":"2025112110401434000_2025.11.19.689260v1.2","doi-asserted-by":"crossref","unstructured":"Bahreini Jangjoo, S. , Lin, J. M. , Etaati, F. , Fearnley, S. , Cloutier, J. F. , Khmaladze, A. and Forni, P. E. (2021). Automated quantification of vomeronasal glomeruli number, size, and color composition after immunofluorescent staining. Chem Senses 46.","DOI":"10.1093\/chemse\/bjab039"},{"key":"2025112110401434000_2025.11.19.689260v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1107770108"},{"key":"2025112110401434000_2025.11.19.689260v1.4","doi-asserted-by":"crossref","unstructured":"Daverkausen-Fischer, L. , Draga, M. and Prols, F . (2022). Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum. Int J Mol Sci 23.","DOI":"10.3390\/ijms23105576"},{"key":"2025112110401434000_2025.11.19.689260v1.5","first-page":"2001","article-title":"Single cell transcriptomics of vomeronasal neuroepithelium reveals a differential endoplasmic reticulum environment amongst neuronal subtypes","volume":"2024","year":"2024","journal-title":"bioRxiv"},{"key":"2025112110401434000_2025.11.19.689260v1.6","first-page":"2010","article-title":"Cnpy1 is a candidate endoplasmic reticulum chaperone of Vomeronasal type 2 GPCRs","volume":"2025","year":"2025","journal-title":"bioRxiv"},{"key":"2025112110401434000_2025.11.19.689260v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018140108"},{"key":"2025112110401434000_2025.11.19.689260v1.8","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.mcn.2013.04.008","article-title":"Convergence of FPR-rs3-expressing neurons in the mouse accessory olfactory bulb","volume":"56","year":"2013","journal-title":"Mol Cell Neurosci"},{"key":"2025112110401434000_2025.11.19.689260v1.9","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12392"},{"key":"2025112110401434000_2025.11.19.689260v1.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1245-11.2011"},{"key":"2025112110401434000_2025.11.19.689260v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2009.06.010"},{"key":"2025112110401434000_2025.11.19.689260v1.12","doi-asserted-by":"crossref","unstructured":"Hills, M. H. , Ma, L. , Fang, A. , Chiremba, T. , Malloy, S. , Scott, A. R. , Perera, A. G. and Yu, C. R. (2024). Molecular, cellular, and developmental organization of the mouse vomeronasal organ at single cell resolution. Elife 13.","DOI":"10.7554\/eLife.97356.3"},{"key":"2025112110401434000_2025.11.19.689260v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.01.055"},{"key":"2025112110401434000_2025.11.19.689260v1.14","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02242"},{"key":"2025112110401434000_2025.11.19.689260v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3297"},{"key":"2025112110401434000_2025.11.19.689260v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03829-3"},{"key":"2025112110401434000_2025.11.19.689260v1.17","doi-asserted-by":"crossref","unstructured":"Katreddi, R. R. , Taroc, E. Z. M. , Hicks, S. M. , Lin, J. M. , Liu, S. T. , Xiang, M. Q. and Forni, P. E. (2022). Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents. Development 14G.","DOI":"10.1101\/2021.10.26.466003"},{"key":"2025112110401434000_2025.11.19.689260v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAD347"},{"key":"2025112110401434000_2025.11.19.689260v1.19","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3765-07.2007"},{"key":"2025112110401434000_2025.11.19.689260v1.20","first-page":"2011","article-title":"Following the p63\/Keratin5 Basal Cells in the Sensory and Non-sensory Epithelia of The Vomeronasal Organ","volume":"2023","year":"2023","journal-title":"bioRxiv"},{"key":"2025112110401434000_2025.11.19.689260v1.21","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1007\/s11033-025-10269-w","article-title":"The role of canopy family proteins: biological mechanism and disease function","volume":"52","year":"2025","journal-title":"Mol Biol Rep"},{"key":"2025112110401434000_2025.11.19.689260v1.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904464106"},{"key":"2025112110401434000_2025.11.19.689260v1.23","doi-asserted-by":"crossref","unstructured":"Lin, J. M. , Mitchell, T. A. , Rothstein, M. , Pehl, A. , Taroc, E. Z. M. , Katreddi, R. R. , Parra, K. E. , Zuloaga, D. G. , Simoes-Costa, M. and Forni, P. E . (2022). Sociosexual behavior requires both activating and repressive roles of Tfap2e\/AP-2epsilon in vomeronasal sensory neurons. Elife 11.","DOI":"10.7554\/eLife.77259"},{"key":"2025112110401434000_2025.11.19.689260v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2018.06.007"},{"key":"2025112110401434000_2025.11.19.689260v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"2025112110401434000_2025.11.19.689260v1.26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1017248108"},{"key":"2025112110401434000_2025.11.19.689260v1.27","doi-asserted-by":"crossref","unstructured":"Montani, G. , Tonelli, S. , Sanghez, V. , Ferrari, P. F. , Palanza, P. , Zimmer, A. and Tirindelli, R. (2013). Aggressive behaviour and physiological responses to pheromones are strongly impaired in mice deficient for the olfactory G-protein -subunit G8. J Physiol 5G1, 3949-3962.","DOI":"10.1113\/jphysiol.2012.247528"},{"key":"2025112110401434000_2025.11.19.689260v1.28","doi-asserted-by":"crossref","unstructured":"Naik, A. S. , Lin, J. M. , Taroc, E. Z. M. , Katreddi, R. R. , Frias, J. A. , Lemus, A. A. , Sammons, M. A. and Forni, P. E . (2020). Smad4-dependent morphogenic signals control the maturation and axonal targeting of basal vomeronasal sensory neurons to the accessory olfactory bulb. Development 147.","DOI":"10.1242\/dev.184036"},{"key":"2025112110401434000_2025.11.19.689260v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-015-2283-8"},{"key":"2025112110401434000_2025.11.19.689260v1.30","doi-asserted-by":"publisher","DOI":"10.1242\/dev.087262"},{"key":"2025112110401434000_2025.11.19.689260v1.31","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2017.00187"},{"key":"2025112110401434000_2025.11.19.689260v1.32","doi-asserted-by":"crossref","unstructured":"Riviere, S. , Challet, L. , Fluegge, D. , Spehr, M. and Rodriguez, I . (2009). Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 45G, 574-577.","DOI":"10.1038\/nature08029"},{"key":"2025112110401434000_2025.11.19.689260v1.33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200216784"},{"key":"2025112110401434000_2025.11.19.689260v1.34","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1002\/pro.3635","article-title":"Characterization of CNPY5 and its family members","volume":"28","year":"2019","journal-title":"Protein Sci"},{"key":"2025112110401434000_2025.11.19.689260v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.08.025"},{"key":"2025112110401434000_2025.11.19.689260v1.36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024462"},{"key":"2025112110401434000_2025.11.19.689260v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-26831-5"},{"key":"2025112110401434000_2025.11.19.689260v1.38","doi-asserted-by":"crossref","unstructured":"Stowers, L. , Holy, T. E. , Meister, M. , Dulac, C. and Koentges, G . (2002). Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 2G5, 1493-1500.","DOI":"10.1126\/science.1069259"},{"key":"2025112110401434000_2025.11.19.689260v1.39","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201906047"},{"key":"2025112110401434000_2025.11.19.689260v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2023.10.020"},{"key":"2025112110401434000_2025.11.19.689260v1.41","doi-asserted-by":"crossref","first-page":"e110501","DOI":"10.15252\/embj.2021110501","article-title":"Neuron-specific translational control shift ensures proteostatic resilience during ER stress","volume":"41","year":"2022","journal-title":"EMBO J"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.19.689260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T10:03:28Z","timestamp":1768471408000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.19.689260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":41,"URL":"https:\/\/doi.org\/10.1101\/2025.11.19.689260","relation":{},"subject":[],"published":{"date-parts":[[2025,11,19]]},"subtype":"preprint"}}