{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:45:08Z","timestamp":1791207908863,"version":"4.1.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,7,3]]},"abstract":"<jats:p>\n                    DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1] is an orphan nuclear receptor that represses transcription by steroidogenic factor-1 (SF-1), a factor that regulates expression of multiple steroidogenic enzymes and other genes involved in reproduction. Mutations in the human\n                    <jats:italic>DAX1<\/jats:italic>\n                    gene (also known as\n                    <jats:italic>AHC<\/jats:italic>\n                    ) cause the X-linked syndrome AHC, a disorder that is associated with hypogonadotropic hypogonadism also. Characterization of\n                    <jats:italic>Dax1<\/jats:italic>\n                    -deficient male mice revealed primary testicular defects that included Leydig cell hyperplasia (LCH) and progressive degeneration of the germinal epithelium, leading to infertility. In this study, we investigated the effect of\n                    <jats:italic>Dax1<\/jats:italic>\n                    disruption on the expression profile of various steroidogenic enzyme genes in Leydig cells isolated from\n                    <jats:italic>Dax1<\/jats:italic>\n                    -deficient male mice. Expression of the aromatase (\n                    <jats:italic>Cyp19<\/jats:italic>\n                    ) gene, which encodes the enzyme that converts testosterone to estradiol, was increased significantly in the Leydig cells isolated from mutant mice, whereas the expression of other proteins (e.g.,\n                    <jats:italic>StAR<\/jats:italic>\n                    and\n                    <jats:italic>Cyp11a<\/jats:italic>\n                    ) was not altered. In\n                    <jats:italic>in vitro<\/jats:italic>\n                    transfection studies, DAX-1 repressed the SF-1-mediated transactivation of the\n                    <jats:italic>Cyp19<\/jats:italic>\n                    promoter but did not inhibit the\n                    <jats:italic>StAR<\/jats:italic>\n                    or\n                    <jats:italic>Cyp11a<\/jats:italic>\n                    promoters. Elevated\n                    <jats:italic>Cyp19<\/jats:italic>\n                    expression was accompanied by increased intratesticular levels of estradiol. Administration of tamoxifen, a selective estrogen-receptor modulator, restored fertility to the\n                    <jats:italic>Dax1<\/jats:italic>\n                    -deficient male mice and partially corrected LCH, suggesting that estrogen excess contributes to LCH and infertility. Based on these\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    analyses, aromatase seems to be a physiologic target of Dax-1 in Leydig cells, and increased\n                    <jats:italic>Cyp19<\/jats:italic>\n                    expression may account, in part, for the infertility and LCH in\n                    <jats:italic>Dax1<\/jats:italic>\n                    -deficient mice.\n                  <\/jats:p>","DOI":"10.1073\/pnas.141543298","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"7988-7993","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":115,"title":["Aromatase (\n                    <i>Cyp19<\/i>\n                    ) expression is up-regulated by targeted disruption of\n                    <i>Dax1<\/i>"],"prefix":"10.1073","volume":"98","author":[{"given":"Zhen J.","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baxter","family":"Jeffs","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Ito","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Achermann","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard N.","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale B.","family":"Hales","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Larry","family":"Jameson","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611; and University of Illinois, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,6,26]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0894-497"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0496-404"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1997.tb18368.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118866"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(75)80978-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1006\/bmme.1995.1049"},{"key":"e_1_3_3_7_2","first-page":"1261","volume":"10","author":"Ikeda Y","year":"1996","unstructured":"Y Ikeda, A Swain, T J Weber, K E Hentges, E Zanaria, E Lalli, K T Tamai, P Sassone-Corsi, R Lovell-Badge, G Camerino, K L Parker Mol Endocrinol 10, 1261\u20131272 (1996).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_8_2","first-page":"654","volume":"8","author":"Ikeda Y","year":"1994","unstructured":"Y Ikeda, W H Shen, H A Ingraham, K L Parker Mol Endocrinol 8, 654\u2013662 (1994).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90050-7"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0039-128X(96)00006-2"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90211-9"},{"key":"e_1_3_3_12_2","first-page":"1233","volume":"9","author":"Luo X","year":"1995","unstructured":"X Luo, Y Ikeda, D A Schlosser, K L Parker Mol Endocrinol 9, 1233\u20131239 (1995).","journal-title":"Mol Endocrinol"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002040104"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.24.10939"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.3.1476"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/36899"},{"key":"e_1_3_3_17_2","first-page":"287","volume-title":"The Leydig Cell","author":"Sundaram K","year":"1996","unstructured":"K Sundaram, N Kumar The Leydig Cell, eds A Payne, M Hardy, L Russell (Cache River Press, Vienna, IL), pp. 287\u2013306 (1996)."},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/3822"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)60944-5"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo-98-2-505"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.12.2.0059"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.7.7545"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00226a004"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-53-2-412"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.10.7026"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.6.8187"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7212"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(73)90341-3"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.7.2.725-737.1987"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)74364-6"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.12.5.0107"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.139.10.6217"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.5.2949"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.13.4910-4921.2000"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041290218"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod46.3.335"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0900093"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(94)90191-0"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90251-8"},{"key":"e_1_3_3_41_2","first-page":"14","volume":"48","author":"Juriansz R L","year":"1988","unstructured":"R L Juriansz, R A Huseby, R B Wilcox Cancer Res 48, 14\u201318 (1988).","journal-title":"Cancer Res"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64736-0"},{"key":"e_1_3_3_43_2","first-page":"54","volume":"51","author":"Rajpert-De Meyts E","year":"1999","unstructured":"E Rajpert-De Meyts, M Schwartz, N E Skakkebaek Horm Res 51, Suppl. 2, 54\u201374 (1999).","journal-title":"Horm Res"},{"key":"e_1_3_3_44_2","first-page":"4501","volume":"84","author":"Seminara S B","year":"1999","unstructured":"S B Seminara, J C Achermann, M Genel, J L Jameson, W F Crowley J Clin Endocrinol Metab 84, 4501\u20134509 (1999).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199707103370204"},{"key":"e_1_3_3_46_2","first-page":"3689","volume":"80","author":"Morishima A","year":"1995","unstructured":"A Morishima, M M Grumbach, E R Simpson, C Fisher, K Qin J Clin Endocrinol Metab 80, 3689\u20133698 (1995).","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199410203311604"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.14.7986"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/37352"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-128X(99)00041-0"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.141543298","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T00:27:22Z","timestamp":1649809642000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.141543298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,6,26]]},"references-count":50,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2001,7,3]]}},"alternative-id":["10.1073\/pnas.141543298"],"URL":"https:\/\/doi.org\/10.1073\/pnas.141543298","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,6,26]]},"assertion":[{"value":"2000-11-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-06-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}