{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:16:35Z","timestamp":1790997395535,"version":"4.1.0"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T00:00:00Z","timestamp":1701907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["21K17219"],"award-info":[{"award-number":["21K17219"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Koshiyama Research Grant","award":["21K17219"],"award-info":[{"award-number":["21K17219"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cdc42 is a small GTPase essential for the cell cycle, morphogenesis, and cell adhesion, and it is involved in the polarity of epithelial cells. However, the functional roles of Cdc42 in exocrine glands, such as the maintenance of acini and water secretion, are not yet well understood. In this study, we generated acinar-cell-specific Cdc42 conditional knockout (Cdc42cKO) mice to assess their maintenance of acinar cells and physiological functions in the salivary glands (SGs) and lacrimal glands (LGs). Our data revealed that the loss of Cdc42 altered the luminal structures to bulging structures and induced acinar cell apoptosis in both the parotid glands (PGs) and LGs of Cdc42cKO mice. Interestingly, saliva secretion in response to pilocarpine stimulation was decreased in the Cdc42cKO group, whereas tear secretion was increased. Consistent with the water secretion results, protein expression of the water channel AQP5 in acinar cells was also decreased in the PGs but conversely increased in the LGs. Moreover, the changes that increased AQP5 expression in LGs occurred in the acinar cells rather than the duct cells. The present study demonstrates that Cdc42 is involved in the structural and survival maintenance of acinar cells in SGs and LGs. On the other hand, depletion of Cdc42 caused the opposite physiological phenomena between PGs and LGs.<\/jats:p>","DOI":"10.3390\/ijms242417220","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T03:35:31Z","timestamp":1701920131000},"page":"17220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of Cdc42 in Exocrine Acini Decreases Saliva Secretion but Increases Tear Secretion\u2014A Potential Model of Exocrine Gland Senescence"],"prefix":"10.3390","volume":"24","author":[{"given":"Haruna","family":"Nagase","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Shitara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8182-3150","authenticated-orcid":false,"given":"Yuta","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keitaro","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Kashimata","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/1097-0142(19910315)67:6<1539::AID-CNCR2820670613>3.0.CO;2-Q","article-title":"Radiation apoptosis of serous acinar cells of salivary and lacrimal glands","volume":"67","author":"Stephens","year":"1991","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13075-017-1228-x","article-title":"Identification of potential saliva and tear biomarkers in primary Sjogren\u2019s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis","volume":"19","author":"Aqrawi","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Aqrawi, L.A., Chen, X., Hynne, H., Amdal, C., Reppe, S., Aass, H.C.D., Rykke, M., Hove, L.H., Young, A., and Herlofson, B.B. (2020). Cytokines Explored in Saliva and Tears from Radiated Cancer Patients Correlate with Clinical Manifestations, Influencing Important Immunoregulatory Cellular Pathways. Cells, 9.","DOI":"10.3390\/cells9092050"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"787193","DOI":"10.3389\/fphar.2021.787193","article-title":"Proteomics Analysis of Tears and Saliva from Sjogren\u2019s Syndrome Patients","volume":"12","author":"Das","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/sj.bdj.4812740","article-title":"Oral Medicine\u2014Update for the dental practitioner. Dry mouth and disorders of salivation","volume":"199","author":"Scully","year":"2005","journal-title":"Br. Dent. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1067\/mpr.2001.113778","article-title":"A review of saliva: Normal composition, flow, and function","volume":"85","author":"Humphrey","year":"2001","journal-title":"J. Prosthet. Dent."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108115","DOI":"10.1016\/j.exer.2020.108115","article-title":"Biological functions of tear film","volume":"197","author":"Pflugfelder","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1089\/ten.tea.2020.0184","article-title":"Building a Functional Salivary Gland for Cell-Based Therapy: More than Secretory Epithelial Acini","volume":"26","author":"Barrows","year":"2020","journal-title":"Tissue Eng. Part A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1242\/jcs.01115","article-title":"Cdc42\u2014The centre of polarity","volume":"117","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S0960-9822(00)00571-6","article-title":"Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability","volume":"10","author":"Chen","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1091\/mbc.E18-10-0615","article-title":"Cdc42 negatively regulates endocytosis during apical membrane maintenance in live animals","volume":"30","author":"Shitara","year":"2019","journal-title":"Mol. Biol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1006\/dbio.1996.8454","article-title":"Mist1: A novel basic helix-loop-helix transcription factor exhibits a developmentally regulated expression pattern","volume":"182","author":"Lemercier","year":"1997","journal-title":"Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/(SICI)1097-0185(20000601)259:2<157::AID-AR6>3.0.CO;2-0","article-title":"Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis","volume":"259","author":"Pin","year":"2000","journal-title":"Anat. Rec."},{"key":"ref_14","first-page":"2517","article-title":"Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland","volume":"144","author":"Farmer","year":"2017","journal-title":"Development"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1177\/36.9.2841372","article-title":"Immunohistochemical localization of Na+, K+-ATPase in rodent and human salivary and lacrimal glands","volume":"36","author":"Winston","year":"1988","journal-title":"J. Histochem. Cytochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/S0140-6736(00)04140-4","article-title":"Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjogren\u2019s syndrome","volume":"357","author":"Tsubota","year":"2001","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1080\/02713680802262819","article-title":"Altered distribution of aquaporin 5 and its C-terminal binding protein in the lacrimal glands of a mouse model for Sj\u00f6gren\u2019s syndrome","volume":"33","author":"Ohashi","year":"2008","journal-title":"Curr. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3389\/fphys.2020.01010","article-title":"Expression Profiles of CircRNA and mRNA in Lacrimal Glands of AQP5\u2212\/\u2212 Mice With Primary Dry Eye","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1267\/ahc.12018","article-title":"Function of the membrane water channel aquaporin-5 in the salivary gland","volume":"45","author":"Matsuzaki","year":"2012","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1080\/02713680701733076","article-title":"The difference of aquaporin 5 distribution in acinar and ductal cells in lacrimal and parotid glands","volume":"32","author":"Sasaki","year":"2007","journal-title":"Curr. Eye Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino, C., Parisis, D., Chivasso, C., Hajiabbas, M., Soyfoo, M.S., and Delporte, C. (2023). Aquaporin-5 Dynamic Regulation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031889"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00424-012-1183-y","article-title":"E2f1-deficient NOD\/SCID mice have dry mouth due to a change of acinar\/duct structure and the down-regulation of AQP5 in the salivary gland","volume":"465","author":"Satoh","year":"2013","journal-title":"Pflug. Arch."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F309","DOI":"10.1152\/ajprenal.00001.2011","article-title":"Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase","volume":"301","author":"Li","year":"2011","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1155\/S0962935195000020","article-title":"Apoptosis and inflammation","volume":"4","author":"Haanen","year":"1995","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e02583","DOI":"10.7554\/eLife.02583","article-title":"Keeping inflammation at bay","volume":"25","author":"Wallach","year":"2014","journal-title":"eLife"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1006\/dbio.2001.0473","article-title":"Sgn1, a basic helix-loop-helix transcription factor delineates the salivary gland duct cell lineage in mice","volume":"240","author":"Yoshida","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2142","DOI":"10.1038\/cddis.2016.51","article-title":"Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp\/stress fibers\/YAP pathway","volume":"7","author":"Huang","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"367","DOI":"10.3324\/haematol.2009.006890","article-title":"Rho GTPase Cdc42 is essential for human T-cell development","volume":"95","author":"Smits","year":"2010","journal-title":"Haematologica"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1007\/s10528-022-10223-6","article-title":"CDC42 Regulates Cell Proliferation and Apoptosis in Bladder Cancer via the IQGAP3-Mediated Ras\/ERK Pathway","volume":"60","author":"Li","year":"2022","journal-title":"Biochem. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8329","DOI":"10.18632\/aging.102322","article-title":"Involvement of adiponectin in age-related increases in tear production in mice","volume":"11","author":"Shikama","year":"2019","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.ajpath.2013.11.019","article-title":"Ocular surface disease and dacryoadenitis in aging C57BL\/6 mice","volume":"184","author":"McClellan","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.5357\/koubyou.74.131","article-title":"Structural features of submandibular glands in the elderly","volume":"74","author":"Yue","year":"2007","journal-title":"Kokubyo Gakkai Zasshi"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s10522-022-10008-9","article-title":"Role of a small GTPase Cdc42 in aging and age-related diseases","volume":"24","author":"Umbayev","year":"2023","journal-title":"Biogerontology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1073\/pnas.0609149104","article-title":"Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes","volume":"104","author":"Wang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1113\/JP280090","article-title":"Arginase 1 is involved in lacrimal hyposecretion in male NOD mice, a model of Sjogren\u2019s syndrome, regardless of dacryoadenitis status","volume":"598","author":"Ohno","year":"2020","journal-title":"J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1093\/glycob\/cwaa060","article-title":"Reliable and sensitive detection of glycosaminoglycan chains with immunoblots","volume":"31","author":"Nagase","year":"2021","journal-title":"Glycobiology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/jb\/mvaa016","article-title":"Old but not obsolete: An enhanced high-speed immunoblot","volume":"168","author":"Higashi","year":"2020","journal-title":"J. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17220\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:34:33Z","timestamp":1760132073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,7]]},"references-count":38,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417220"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417220","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,7]]}}}