{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:23:10Z","timestamp":1790828590002,"version":"4.1.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T00:00:00Z","timestamp":1644796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RO1HD040793"],"award-info":[{"award-number":["RO1HD040793"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RO1DK097124"],"award-info":[{"award-number":["RO1DK097124"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Boston Area Diabetes and Endocrinology Research Center","award":["DK57521"],"award-info":[{"award-number":["DK57521"]}]},{"name":"Center for the Study of Inflammatory Bowel Disease","award":["DK43351"],"award-info":[{"award-number":["DK43351"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,5,17]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This study aimed to clarify the functional role of mitogen-activated protein kinase (MAPK)\/extracellular signal-regulated kinase (ERK1\/2)-signaling pathway in the expression and localization of connexin 43 (Cx43). Mice were treated with the mitogen-activated protein kinase kinase (MEK1\/2) inhibitor, PD325901, which induced a progressive decrease in ERK1\/2 phosphorylation (pERK) in the proximal epididymis of the mice, without affecting total ERK level. Cx43 staining with punctuated reactive sites was observed in the basolateral membranes in the initial segment (IS) of mouse epididymis. However, PD325901 induced a significant decrease in Cx43 labeling in the basolateral membranes. Interestingly, Cx43, which was undetectable in the apical region of epididymis under control conditions, showed a significant increase in the apical region after PD 325901 treatment. To confirm whether Cx43 was present in tight junctions (TJs) after PD 325901 treatment, PD325901-treated epididymis samples were double-labeled with Cx43 and zonula occludens (ZO)-1 (a TJ protein marker). Thereafter, confocal microscopy showed the colocalization of Cx43 and ZO-1 in the epididymis after PD325901 treatment. Collectively, our results indicated that PD325901 treatment induced a significant increase in Cx43 localization on TJs, where it was colocalized with ZO-1. Therefore, the study suggested that ERK phosphorylation is essential for the proper expression and localization of the gap junction (GJ) protein, and that the relationship between GJs and TJs could play an important role in establishing and maintaining microenvironmental homeostasis for sperm maturation in the IS of mouse epididymis.<\/jats:p>","DOI":"10.1093\/biolre\/ioac034","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T10:57:44Z","timestamp":1644836264000},"page":"919-927","source":"Crossref","is-referenced-by-count":10,"title":["The MAPK\/ERK signaling pathway regulates the expression and localization of Cx43 in mouse proximal epididymis"],"prefix":"10.1093","volume":"106","author":[{"given":"Bongki","family":"Kim","sequence":"first","affiliation":[{"name":"Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"},{"name":"Department of Animal Resources Science, Kongju National University, Yesan, Chungcheongnam-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Breton","sequence":"additional","affiliation":[{"name":"Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,14]]},"reference":[{"key":"2022051716202175000_ref1","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1016\/j.biocel.2008.04.009","article-title":"The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells","volume":"40","author":"Ramos","year":"2008","journal-title":"Int J Biochem Cell Biol"},{"key":"2022051716202175000_ref2","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1210\/endo.131.6.1446643","article-title":"Characterization of epidermal growth factor in mouse testis","volume":"131","author":"Radhakrishnan","year":"1992","journal-title":"Endocrinology"},{"key":"2022051716202175000_ref3","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1095\/biolreprod58.1.160","article-title":"Functional expression and localization of vascular endothelial growth factor and its receptors in the human epididymis","volume":"58","author":"Ergun","year":"1998","journal-title":"Biol Rprod"},{"key":"2022051716202175000_ref4","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1095\/biolreprod58.1.197","article-title":"Regulation of gamma-glutamyl transpeptidase catalytic activity and protein level in the initial segment of the rat epididymis by testicular factors: role of basic fibroblast growth factor","volume":"58","author":"Lan","year":"1998","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref5","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/j.1939-4640.1999.tb02531.x","article-title":"TGF-\u03b2 could be involved in paracrine actions in the epididymis of the marmoset monkey (Callithrix jacchus)","volume":"20","author":"Bomgardner","year":"1999","journal-title":"J Androl"},{"key":"2022051716202175000_ref6","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/(SICI)1098-2795(199906)53:2<188::AID-MRD8>3.0.CO;2-O","article-title":"p53 independent, region-specific epithelial apoptosis is induced in the rat epididymis by deprivation of luminal factors","volume":"53","author":"Turner","year":"1999","journal-title":"Mol Reprod Dev"},{"key":"2022051716202175000_ref7","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1679\/aohc.52.299","article-title":"Early degeneration of the epithelial cells in the initial segment of the epididymal duct in mice after efferent duct cutting","volume":"52","author":"Abe","year":"1989","journal-title":"Arch Histol Cytol"},{"key":"2022051716202175000_ref8","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1365-2605.1983.tb00326.x","article-title":"Early effects of efferent ductule ligation on the proximal segment of the rat epididymis","volume":"6","author":"Nicander","year":"1983","journal-title":"Int J Androl"},{"key":"2022051716202175000_ref9","first-page":"211","article-title":"Regulation of apoptotic cell death in the rat epididymis","volume":"53","author":"Robaire","year":"1998","journal-title":"J Reprod Fertil Suppl"},{"key":"2022051716202175000_ref10","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/B978-012515400-0\/50027-0","volume-title":"Knobil and Neill's Physiology of Reproduction","author":"Robaire","year":"2006","edition":"3rd"},{"key":"2022051716202175000_ref11","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1095\/biolreprod.110.085613","article-title":"P-MAPK1\/3 and DUSP6 regulate epididymal cell proliferation and survival in a region-specific manner in mice","volume":"83","author":"Xu","year":"2010","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.112.107185","article-title":"The role of fibroblast growth factor receptor substrate 2 (FRS2) in the regulation of two activity levels of the components of the extracellular signal-regulated kinase (ERK) pathway in the mouse epididymis","volume":"89","author":"Xu","year":"2013","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref13","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1095\/biolreprod.110.090324","article-title":"Testicular lumicrine factors regulate ERK, STAT, and NFKB pathways in the initial segment of the rat epididymis to prevent apoptosis","volume":"84","author":"Xu","year":"2011","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.114.123943","article-title":"Role of testicular luminal factors on basal cell elongation and proliferation in the mouse epididymis","volume":"92","author":"Kim","year":"2015","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref15","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0015-0282(16)49528-2","article-title":"The role of the human epididymis in sperm maturation and sperm storage as reflected in the consequences of epididymovasostomy","volume":"46","author":"Schoysman","year":"1986","journal-title":"Fertil Steril"},{"key":"2022051716202175000_ref16","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/ar.1091910409","article-title":"Regional differentiation of cell junctions in the excurrent duct epithelium of the rat testis as revealed by freeze-fracture","volume":"191","author":"Suzuki","year":"1978","journal-title":"Anat Rec"},{"key":"2022051716202175000_ref17","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/jemt.1070300105","article-title":"Structure and turnover of junctional complexes between principal cells of the rat epididymis","volume":"30","author":"Cyr","year":"1995","journal-title":"Microsc Res Tech"},{"key":"2022051716202175000_ref18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.115.134965","article-title":"The MAPK\/ERK-Signaling pathway regulates the expression and distribution of tight junction proteins in the mouse proximal epididymis","volume":"94","author":"Kim","year":"2016","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref19","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1478-811X-7-4","article-title":"Connexins: a myriad of functions extending beyond assembly of gap junction channels","volume":"7","author":"Dbouk","year":"2009","journal-title":"Cell Commun Signal"},{"key":"2022051716202175000_ref20","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1098\/rstb.2009.0114","article-title":"Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis","volume":"365","author":"Pointis","year":"2010","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"2022051716202175000_ref21","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1210\/endo.137.4.8625926","article-title":"Immunocytochemical localization and regulation of connexin43 in the adult rat epididymis","volume":"137","author":"Cyr","year":"1996","journal-title":"Endocrinology"},{"key":"2022051716202175000_ref22","doi-asserted-by":"crossref","first-page":"325","DOI":"10.4161\/spmg.1.4.18948","article-title":"Connexins and pannexins: coordinating cellular communication in the testis and epididymis","volume":"1","author":"Cyr","year":"2011","journal-title":"Spermatogenesis"},{"key":"2022051716202175000_ref23","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1242\/jcs.103.1.81","article-title":"Cell-, age-and stage-dependent distribution of connexin43 gap junctions in testes","volume":"103","author":"Risley","year":"1992","journal-title":"J Cell Sci"},{"key":"2022051716202175000_ref24","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1095\/biolreprod65.3.829","article-title":"Failure of spermatogenesis in mice lacking connexin43","volume":"65","author":"Roscoe","year":"2001","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref25","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2353\/ajpath.2007.061171","article-title":"A sertoli cell-specific knockout of connexin43 prevents initiation of spermatogenesis","volume":"171","author":"Brehm","year":"2007","journal-title":"Am J Pathol"},{"key":"2022051716202175000_ref26","doi-asserted-by":"crossref","first-page":"e630","DOI":"10.1111\/j.1365-2605.2011.01224.x","article-title":"Male reproductive system defects and subfertility in a mutant mouse model of oculodentodigital dysplasia 1","volume":"34","author":"Gregory","year":"2011","journal-title":"Int J Androl"},{"key":"2022051716202175000_ref27","doi-asserted-by":"crossref","first-page":"6325","DOI":"10.1523\/JNEUROSCI.1120-18.2019","article-title":"The inhibition of RasGRF2, but not RasGRF1, alters cocaine reward in mice","volume":"39","author":"Bernardi","year":"2019","journal-title":"J Neurosci"},{"key":"2022051716202175000_ref28","doi-asserted-by":"crossref","first-page":"10666","DOI":"10.1038\/ncomms10666","article-title":"Tyrosine kinase-mediated axial motility of basal cells revealed by intravital imaging","volume":"7","author":"Roy","year":"2016","journal-title":"Nat Commun"},{"key":"2022051716202175000_ref29","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/j.1439-0272.1993.tb02744.x","article-title":"Effect of a nonsteroidal antiandrogen, flutamide on intraluminal acidification in rat testis and epididymis","volume":"25","author":"Caflisch","year":"1993","journal-title":"Andrologia"},{"key":"2022051716202175000_ref30","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0960-0760(94)90259-3","article-title":"The effect of androgens and antiandrogens on the immunohistochemical localization of the androgen receptor in accessory reproductive organs of male rats","volume":"48","author":"Paris","year":"1994","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2022051716202175000_ref31","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1095\/biolreprod66.6.1716","article-title":"Expression of aquaporin 9 in the adult rat epididymal epithelium is modulated by androgens","volume":"66","author":"Pastor-Soler","year":"2002","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref32","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1210\/endo.135.3.7915228","article-title":"Expression of multiple gamma-glutamyl transpeptidase messenger ribonucleic acid transcripts in the adult rat epididymis is differentially regulated by androgens and testicular factors in a region-specific manner","volume":"135","author":"Palladino","year":"1994","journal-title":"Endocrinology"},{"key":"2022051716202175000_ref33","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1113\/jphysiol.2012.230581","article-title":"ATP secretion in the male reproductive tract: essential role of CFTR","volume":"590","author":"Ruan","year":"2012","journal-title":"J Physiol"},{"key":"2022051716202175000_ref34","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1095\/biolreprod.110.088559","article-title":"The fused toes locus is essential for somatic-germ cell interactions that foster germ cell maturation in developing gonads in mice","volume":"84","author":"Kim","year":"2011","journal-title":"Biol Reprod"},{"key":"2022051716202175000_ref35","doi-asserted-by":"crossref","first-page":"C33","DOI":"10.1152\/ajpcell.00111.2002","article-title":"Expression of multiple connexins in the rat epididymis indicates a complex regulation of gap junctional communication","volume":"284","author":"Dufresne","year":"2003","journal-title":"Am J Physiol Cell Physiol"},{"key":"2022051716202175000_ref36","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1093\/humrep\/des164","article-title":"Epidermal growth factor regulates connexin 43 in the human epididymis: role of gap junctions in azoospermia","volume":"27","author":"Dub\u00e9","year":"2012","journal-title":"Hum Reprod"},{"key":"2022051716202175000_ref37","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.semcdb.2015.12.019","article-title":"Roles of connexins in testis development and spermatogenesis","volume":"50","author":"Kidder","year":"2016","journal-title":"Semin Cell Dev Biol"},{"key":"2022051716202175000_ref38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1242\/jcs.103.1.81","article-title":"Cell-, age- and stage-dependent distribution of connexin43 gap junctions in testes","volume":"103","author":"Risley","year":"1992","journal-title":"J Cell Sci"},{"key":"2022051716202175000_ref39","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1002\/j.1939-4640.1995.tb00552.x","article-title":"The distribution of connexin 43 is associated with the germ cell differentiation and with the modulation of the Sertoli cell junctional barrier in continual (Guinea pig) and seasonal breeders' (mink) testes","volume":"16","author":"Pelletier","year":"1995","journal-title":"J Androl"},{"key":"2022051716202175000_ref40","doi-asserted-by":"crossref","first-page":"17998","DOI":"10.1073\/pnas.1007047107","article-title":"Connexin 43 is critical to maintain the homeostasis of the blood\u2013testis barrier via its effects on tight junction reassembly","volume":"107","author":"Li","year":"2010","journal-title":"Proc Natl Acad Sci"},{"key":"2022051716202175000_ref41","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ydbio.2010.07.014","article-title":"Major involvement of connexin 43 in seminiferous epithelial junction dynamics and male fertility","volume":"346","author":"Carette","year":"2010","journal-title":"Dev Biol"},{"key":"2022051716202175000_ref42","doi-asserted-by":"crossref","first-page":"12725","DOI":"10.1074\/jbc.273.21.12725","article-title":"Direct association of the gap junction protein connexin-43 with ZO-1 in cardiac myocytes","volume":"273","author":"Toyofuku","year":"1998","journal-title":"J Biol Chem"},{"key":"2022051716202175000_ref43","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1210\/endo.140.8.6903","article-title":"Cellular immunolocalization of occludin during embryonic and postnatal development of the mouse testis and epididymis","volume":"140","author":"Cyr","year":"1999","journal-title":"Endocrinology"}],"container-title":["Biology of Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biolreprod\/advance-article-pdf\/doi\/10.1093\/biolre\/ioac034\/42950745\/ioac034.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/106\/5\/919\/43723071\/ioac034.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biolreprod\/article-pdf\/106\/5\/919\/43723071\/ioac034.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T12:44:51Z","timestamp":1700225091000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biolreprod\/article\/106\/5\/919\/6528177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,14]]},"references-count":43,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,2,14]]},"published-print":{"date-parts":[[2022,5,17]]}},"URL":"https:\/\/doi.org\/10.1093\/biolre\/ioac034","relation":{},"ISSN":["0006-3363","1529-7268"],"issn-type":[{"value":"0006-3363","type":"print"},{"value":"1529-7268","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,5]]},"published":{"date-parts":[[2022,2,14]]}}}