{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:58:17Z","timestamp":1790171897286,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japanese Society for the Promotion of Science","award":["KAKENHI no. 17K15543"],"award-info":[{"award-number":["KAKENHI no. 17K15543"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The lumen of the fallopian tube (FT) is lined with columnar epithelium composed of secretory and ciliated cells, both of which are important for reproduction. However, the molecular mechanism regulating cell fate remains controversial. In this study, we established a primary culture system using porcine fallopian tube epithelial cells (FTECs) to study the differentiation mechanism. We found that estrogen promoted the differentiation of multi-ciliated cells (MCCs) through estrogen receptor \u03b2, following the reduction of DLL1, a ligand of Notch. Meanwhile, epidermal growth factor (EGF), a regulator of epithelial homeostasis and differentiation, suppressed ciliogenesis by the activation of Notch signaling. However, the estrogen pathway did not affect the activation of the EGF pathway. Taken together, the differentiation of MMCs in FT depends on the balance of EGF and estrogen signaling, either of which inhibits or stimulates the Notch signaling pathway respectively.<\/jats:p>","DOI":"10.3390\/cells8080933","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T11:22:38Z","timestamp":1566213758000},"page":"933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Estrogen and EGFR Pathways Regulate Notch Signaling in Opposing Directions for Multi-Ciliogenesis in the Fallopian Tube"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1700-7917","authenticated-orcid":false,"given":"Maobi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Iwano","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Graduate School of Medicine, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/humupd\/dml012","article-title":"The reproductive significance of human Fallopian tube cilia","volume":"12","author":"Lyons","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1093\/oxfordjournals.humrep.a138628","article-title":"Comparative immunohistochemical study of oestrogen and progesterone receptors in the fallopian tube and uterus at different stages of the menstrual cycle and the menopause","volume":"9","author":"Amso","year":"1994","journal-title":"Hum. Reprod."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/aja.1001870109","article-title":"Oviductal epithelium of the baboon: hormonal control and the immuno-gold localization of oviduct-specific glycoproteins","volume":"187","author":"Verhage","year":"1990","journal-title":"Am. J. Anat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1093\/humrep\/13.11.3114","article-title":"Induction of a differentiated ciliated cell phenotype in primary cultures of Fallopian tube epithelium","volume":"13","author":"Comer","year":"1998","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0378-5122(83)90020-8","article-title":"Changes in ciliation and cell height in human tubal epithelium in the fertile and post-fertile years","volume":"5","author":"Donnez","year":"1983","journal-title":"Maturitas"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1242\/dev.029249","article-title":"Notch signaling promotes airway mucous metaplasia and inhibits alveolar development","volume":"136","author":"Guseh","year":"2009","journal-title":"Development"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1242\/dev.034884","article-title":"Notch signaling controls the balance of ciliated and secretory cell fates in developing airways","volume":"136","author":"Tsao","year":"2009","journal-title":"Development"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.4049\/jimmunol.1003606","article-title":"MUC5AC expression through bidirectional communication of Notch and epidermal growth factor receptor pathways","volume":"187","author":"Kang","year":"2011","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Valencia-Gattas, M., Conner, G.E., and Fregien, N.L. (2016). Gefitinib, an EGFR tyrosine kinase inhibitor, prevents smoke-mediated ciliated airway epithelial cell loss and promotes their recovery. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160216"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.ccr.2013.10.013","article-title":"Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models","volume":"24","author":"Perets","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1097\/PAS.0b013e3181ef7b16","article-title":"Are all pelvic (nonuterine) serous carcinomas of tubal origin?","volume":"34","author":"Przybycin","year":"2010","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/his.12046","article-title":"Fallopian tube precursors of ovarian low- and high-grade serous neoplasms","volume":"62","author":"Vang","year":"2013","journal-title":"Histopathology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8989","DOI":"10.1038\/ncomms9989","article-title":"The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids","volume":"6","author":"Kessler","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/jmicro\/dfy015","article-title":"TI Workbench, an integrated software package for electrophysiology and imaging","volume":"67","author":"Inoue","year":"2018","journal-title":"Microsc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI27987","article-title":"Estrogen receptors and human disease","volume":"116","author":"Deroo","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1677\/JOE-09-0242","article-title":"The unfolding stories of GPR30, a new membrane-bound estrogen receptor","volume":"204","author":"Maggiolini","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1136\/thx.2003.018879","article-title":"Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium","volume":"59","author":"Burgel","year":"2004","journal-title":"Thorax"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/ncb2241","article-title":"Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta\/Notch pathway","volume":"13","author":"Marcet","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.stem.2011.04.003","article-title":"Notch-dependent differentiation of adult airway basal stem cells","volume":"8","author":"Rock","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1677\/jme.0.0320615","article-title":"Role of foxj1 and estrogen receptor alpha in ciliated epithelial cell differentiation of the neonatal oviduct","volume":"32","author":"Okada","year":"2004","journal-title":"J. Mol. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1073\/pnas.96.6.3081","article-title":"Epidermal growth factor system regulates mucin production in airways","volume":"96","author":"Takeyama","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"32258","DOI":"10.1074\/jbc.M204862200","article-title":"Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor\/Ras\/Raf\/extracellular signal-regulated kinase cascade and Sp1","volume":"277","author":"Perrais","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","article-title":"Notch signaling: cell fate control and signal integration in development","volume":"284","author":"Rand","year":"1999","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12102","DOI":"10.1073\/pnas.1303058110","article-title":"EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype","volume":"110","author":"Shaykhiev","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1101\/gad.975202","article-title":"Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells","volume":"16","author":"Hitoshi","year":"2002","journal-title":"Genes Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24353","DOI":"10.1074\/jbc.M201829200","article-title":"Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression","volume":"277","author":"Liu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.mce.2011.06.043","article-title":"Tumor necrosis factor-alpha activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor alpha","volume":"345","author":"Gori","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.arcmed.2016.07.002","article-title":"Opposite function of ERalpha and ERbeta in controlling 17beta-estradiol-mediated osteogenesis in osteoblasts","volume":"47","author":"Wang","year":"2016","journal-title":"Arch. Med. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1593\/neo.101340","article-title":"Epidermal growth factor and estrogen act by independent pathways to additively promote the release of the angiogenic chemokine CXCL8 by breast tumor cells","volume":"13","author":"Haim","year":"2011","journal-title":"Neoplasia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E331","DOI":"10.1152\/ajpendo.00133.2009","article-title":"Epidermal growth factor receptor cross-talks with ligand-occupied estrogen receptor-alpha to modulate both lactotroph proliferation and prolactin gene expression","volume":"297","author":"Chen","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.270.5241.1491","article-title":"Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase","volume":"270","author":"Kato","year":"1995","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1126\/science.3263702","article-title":"Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors","volume":"242","author":"Yaish","year":"1988","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1158\/0008-5472.CAN-04-1890","article-title":"Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation","volume":"65","author":"Purow","year":"2005","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1097\/CEJ.0000000000000052","article-title":"The effect of estrogen on the proliferation of endometrial cancer cells is mediated by ERRgamma through AKT and ERK1\/2","volume":"23","author":"Sun","year":"2014","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nature15715","article-title":"Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung","volume":"528","author":"Lafkas","year":"2015","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nature14553","article-title":"Parent stem cells can serve as niches for their daughter cells","volume":"523","author":"Tata","year":"2015","journal-title":"Nature"},{"key":"ref_37","first-page":"5985","article-title":"Phosphatidylinositol-3-OH Kinase (PI3K)\/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K","volume":"61","author":"Sun","year":"2001","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/8\/933\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:12:14Z","timestamp":1760188334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/8\/933"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,19]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8]]}},"alternative-id":["cells8080933"],"URL":"https:\/\/doi.org\/10.3390\/cells8080933","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,19]]}}}