{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:50:15Z","timestamp":1791067815214,"version":"4.1.0"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[1999,8,1]],"date-time":"1999-08-01T00:00:00Z","timestamp":933465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1999,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>doublesex (dsx) is unusual among the known sex-determination genes of Drosophila melanogaster in that functional homologs are found in distantly related species. In flies, dsx occupies a position near the bottom of the sex determination hierarchy. It is expressed in male- and female-specific forms and these proteins function as sex-specific transcription factors. In the studies reported here, we have ectopically expressed the female Dsx protein (DsxF) from a constitutive promoter and examined its regulatory activities independent of other upstream factors involved in female sex determination. We show that it functions as a positive regulator of female differentiation and a negative regulator of male differentiation. As predicted by the DNA-binding properties of the Dsx protein, DsxF and DsxM compete with each other for the regulation of target genes. In addition to directing sex-specific differentiation, DsxF plays an important role in sexual behavior. Wild-type males ectopically expressing DsxF are actively courted by other males. This acquisition of feminine sex appeal is likely due to the induction of female pheromones by DsxF. More extreme behavioral abnormalities are observed when DsxF is ectopically expressed in dsx- XY animals; these animals are not only courted by, but also copulate with, wild-type males. Finally, we provide evidence that intersex is required for the feminizing activities of DsxF and that it is not regulated by the sex-specific splicing cascade.<\/jats:p>","DOI":"10.1093\/genetics\/152.4.1653","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T03:09:00Z","timestamp":1619579340000},"page":"1653-1667","source":"Crossref","is-referenced-by-count":115,"title":["Analysis of the Doublesex Female Protein in Drosophila melanogaster: Role in Sexual Differentiation and Behavior and Dependence on Intersex"],"prefix":"10.1093","volume":"152","author":[{"given":"Julie A","family":"Waterbury","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, New Jersey, 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry L","family":"Jackson","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry Department, Montana State University, Bozeman, Montana 59717-0310"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Schedl","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, New Jersey, 08544"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[1999,8,1]]},"reference":[{"key":"2022011809362536800_R1","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1002\/j.1460-2075.1995.tb07105.x","article-title":"Three protein binding sites form an enhancer that regulates sex- and fat body-specific transcription of Drosophila yolk protein genes","volume":"14","author":"An","year":"1995","journal-title":"EMBO J."},{"key":"2022011809362536800_R2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1101\/gad.9.2.256","article-title":"Integrating sex- and tissue-specific regulation within a single Drosophila enhancer","volume":"9","author":"An","year":"1995","journal-title":"Genes Dev."},{"key":"2022011809362536800_R3","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1128\/MCB.16.6.3106","article-title":"Sex-specific and non-sex-specific oligomerization domains in both of the doublesex transcription factors from Drosophila melanogaster","volume":"16","author":"An","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"2022011809362536800_R4","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/0022-1910(82)90101-9","article-title":"The chemical basis for sex recognition in Drosophila melanogaster","volume":"28","author":"Antony","year":"1982","journal-title":"J. Insect Physiol."},{"key":"2022011809362536800_R5","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1007\/BF01012116","article-title":"Compared behavioral responses of male Drosophila melanogaster (Canton S) to natural and synthetic aphrodisiacs","volume":"11","author":"Antony","year":"1985","journal-title":"J. Chem. Ecol."},{"key":"2022011809362536800_R6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/340521a0","article-title":"Sex in flies: the splice of life","volume":"340","author":"Baker","year":"1989","journal-title":"Nature"},{"key":"2022011809362536800_R7","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/genetics\/94.2.383","article-title":"Sex and the single cell. I. On the action of major loci affecting sex determination in Drosophila melanogaster","volume":"94","author":"Baker","year":"1980","journal-title":"Genetics"},{"key":"2022011809362536800_R8","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1101\/gad.2.4.477","article-title":"A molecular analysis of doublesex, a bifunctional gene that controls both male and female sexual differentiation in Drosophila melanogaster","volume":"2","author":"Baker","year":"1988","journal-title":"Genes Dev."},{"key":"2022011809362536800_R9","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1101\/gad.3.9.1288","article-title":"P-element-mediated enhancer detection: a versatile method to study development in Drosophila","volume":"3","author":"Bellen","year":"1989","journal-title":"Genes Dev."},{"key":"2022011809362536800_R10","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1242\/dev.118.3.797","article-title":"Expression of the Sex-lethal gene is controlled at multiple levels during Drosophila oogenesis","volume":"118","author":"Bopp","year":"1993","journal-title":"Development"},{"key":"2022011809362536800_R11","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/BF00269661","article-title":"Sex determining genes and vitellogenin synthesis in Drosophila melanogaster","volume":"182","author":"Bownes","year":"1981","journal-title":"Mol. Gen. Genet."},{"key":"2022011809362536800_R12","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/0092-8674(89)90633-8","article-title":"Drosophila doublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides","volume":"56","author":"Burtis","year":"1989","journal-title":"Cell"},{"key":"2022011809362536800_R13","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/j.1460-2075.1991.tb07798.x","article-title":"The doublesex proteins of Drosophila melanogaster bind directly to a sex-specific yolk protein gene enhancer","volume":"10","author":"Burtis","year":"1991","journal-title":"EMBO J."},{"key":"2022011809362536800_R14","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1126\/science.163.3873.1356","article-title":"Lipids of Drosophila: a newly detected lipid in the male","volume":"163","author":"Butterworth","year":"1969","journal-title":"Science"},{"key":"2022011809362536800_R15","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1021\/ac00189a019","article-title":"Dimethyl disulfide derivatives of long chain alkenes, alkadienes, and alkatrienes for gas chromatography\/mass spectrometry","volume":"61","author":"Carlson","year":"1989","journal-title":"Anal. Chem."},{"key":"2022011809362536800_R16","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1093\/genetics\/139.4.1649","article-title":"A genetic analysis of intersex, a gene regulating sexual differentiation in Drosophila melanogaster females","volume":"139","author":"Chase","year":"1995","journal-title":"Genetics"},{"key":"2022011809362536800_R17","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1074\/jbc.272.6.3185","article-title":"DNA binding by the male and female doublesex proteins of Drosophila melanogaster","volume":"272","author":"Cho","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2022011809362536800_R18","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1093\/genetics\/90.4.683","article-title":"Two closely linked mutations in Drosophila melanogaster that are lethal to opposite sexes and interact with daughterless","volume":"90","author":"Cline","year":"1978","journal-title":"Genetics"},{"key":"2022011809362536800_R19","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1093\/genetics\/107.2.231","article-title":"Autoregulation functioning of a Drosophila geneproduct that establishes and maintains the sexually determined state","volume":"107","author":"Cline","year":"1984","journal-title":"Genetics"},{"key":"2022011809362536800_R20","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/genetics\/119.4.829","article-title":"Evidence that sisterless-a and sisterless-b are two of several discrete \u201cnumerator elements\u201d of the X\/A sex determination signal in Drosophila that switch Sxl between two alternative stable expression states","volume":"119","author":"Cline","year":"1988","journal-title":"Genetics"},{"key":"2022011809362536800_R21","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1146\/annurev.genet.30.1.637","article-title":"Vive la difference: males vs females in flies vs worms","volume":"30","author":"Cline","year":"1996","journal-title":"Annu. Rev. Genet."},{"key":"2022011809362536800_R22","first-page":"1719","article-title":"Female mate discrimination or male responses to female stimulation?","volume":"50","author":"Cobb","year":"1996","journal-title":"Evolution"},{"key":"2022011809362536800_R23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0376-6357(95)00052-6","article-title":"Evolution and genetic control of mate recognition and stimulation in Drosophila","volume":"35","author":"Cobb","year":"1996","journal-title":"Behav. Processes"},{"key":"2022011809362536800_R24","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0003-3472(05)80778-X","article-title":"Pheromones, mate recognition and courtship stimulation in Drosophila melanogaster species subgroup","volume":"39","author":"Cobb","year":"1990","journal-title":"Animal Behav."},{"key":"2022011809362536800_R25","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1101\/gad.7.1.42","article-title":"Sex-specific transcriptional regulation by the male and female doublesex proteins of Drosophila","volume":"7","author":"Coschigano","year":"1993","journal-title":"Genes Dev."},{"key":"2022011809362536800_R26","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/j.1460-2075.1993.tb05684.x","article-title":"The Drosophila doublesex proteins share a novel zinc finger related DNA binding domain","volume":"12","author":"Erdman","year":"1993","journal-title":"EMBO J."},{"key":"2022011809362536800_R27","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1093\/genetics\/144.4.1639","article-title":"Functional and genetic characterization of the oligomerization and DNA binding properties of the Drosophila doublesex proteins","volume":"144","author":"Erdman","year":"1996","journal-title":"Genetics"},{"key":"2022011809362536800_R28","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1002\/bies.950190413","article-title":"The pheromonal role of cuticular hydrocarbons in Drosophila melanogaster","volume":"19","author":"Ferveur","year":"1997","journal-title":"Bioessays"},{"key":"2022011809362536800_R29","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1098\/rspb.1996.0143","article-title":"Simultaneous influence on male courtship of stimulatory and inhibitory pheromones produced by live sex-mosaic Drosophila melanogaster","volume":"263","author":"Ferveur","year":"1996","journal-title":"Proc. R. Soc. Lond. B Biol. Sci."},{"key":"2022011809362536800_R30","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1126\/science.276.5318.1555","article-title":"Genetic feminization of pheromones and its behavioral consequences in Drosophila males","volume":"276","author":"Ferveur","year":"1997","journal-title":"Science"},{"key":"2022011809362536800_R31","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1073\/pnas.94.3.913","article-title":"dissatisfaction, a gene involved in sex-specific behavior and neural development of Drosophila melanogaster","volume":"94","author":"Finley","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022011809362536800_R32","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/S0896-6273(00)80655-8","article-title":"dissatisfaction encodes a tailless-like nuclear receptor expressed in a subset of CNS neurons controlling Drosophila sexual behavior","volume":"21","author":"Finley","year":"1998","journal-title":"Neuron"},{"key":"2022011809362536800_R33","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1126\/science.8209251","article-title":"The mating of a fly","volume":"264","author":"Hall","year":"1994","journal-title":"Science"},{"key":"2022011809362536800_R34","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/0092-8674(91)90090-L","article-title":"Sex-specific splicing and polyadenylation of dsx pre-mRNA requires a sequence that binds specifically to tra-2 protein in vitro","volume":"65","author":"Hedley","year":"1991","journal-title":"Cell"},{"key":"2022011809362536800_R35","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/(SICI)1097-4695(199608)30:4<454::AID-NEU2>3.0.CO;2-2","article-title":"Male-male courtship behavior induced by ectopic expression of the Drosophila white gene: role of sensory function and age","volume":"30","author":"Hing","year":"1996","journal-title":"J. Neurobiol."},{"key":"2022011809362536800_R36","first-page":"1408","article-title":"Regulated splicing of the Drosophila sex-lethal male exon involves a blockage mechanism","volume":"13","author":"Horabin","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2022011809362536800_R37","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S0022-2836(82)80016-8","article-title":"Transcript maps of Drosophila yolk protein genes","volume":"154","author":"Hung","year":"1982","journal-title":"J. Mol. Biol."},{"key":"2022011809362536800_R38","doi-asserted-by":"crossref","first-page":"9687","DOI":"10.1073\/pnas.93.18.9687","article-title":"Sexual orientation in Drosophila is altered by the satori mutation in the sex-determination gene fruitless that encodes a zinc finger protein with a BTB domain","volume":"93","author":"Ito","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022011809362536800_R39","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/BF01065444","article-title":"A few chemical words exchanged by Drosophila during courtship and mating","volume":"14","author":"Jallon","year":"1984","journal-title":"Behav. Genet."},{"key":"2022011809362536800_R40","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1017\/S0016672300023892","article-title":"Female pheromones in Drosophila melanogaster are controlled by the doublesex locus","volume":"51","author":"Jallon","year":"1988","journal-title":"Genet. Res."},{"key":"2022011809362536800_R41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1006\/dbio.1993.1021","article-title":"A positive role in differentiation for the male doublesex protein of Drosophila","volume":"155","author":"Jursnich","year":"1993","journal-title":"Dev. Biol."},{"key":"2022011809362536800_R42","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1242\/dev.125.14.2641","article-title":"hermaphrodite and doublesex function both dependently and independently to control various aspects of sexual differentiation in Drosophila","volume":"125","author":"Li","year":"1998","journal-title":"Development"},{"key":"2022011809362536800_R43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/genetics\/111.1.89","article-title":"The effect of transformer, doublesex and intersex mutations on the sexual behavior of Drosophila melanogaster","volume":"111","author":"McRobert","year":"1985","journal-title":"Genetics"},{"key":"2022011809362536800_R44","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1242\/dev.125.8.1487","article-title":"Sex-lethal, the master sex-determining gene in Drosophila, is not sex-specifically regulated in Musca domestica","volume":"125","author":"Meise","year":"1998","journal-title":"Development"},{"key":"2022011809362536800_R45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1101\/gad.4.1.89","article-title":"Regulation of sex-specific RNA splicing at the Drosophila doublesex gene: cis-acting mutations in exon sequences alter sex-specific RNA splicing patterns","volume":"4","author":"Nagoshi","year":"1990","journal-title":"Genes Dev."},{"key":"2022011809362536800_R46","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0092-8674(88)90384-4","article-title":"The control of alternative splicing at genes regulating sexual differentiation in D. melanogaster","volume":"53","author":"Nagoshi","year":"1988","journal-title":"Cell"},{"key":"2022011809362536800_R47","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/B978-0-409-90042-2.50028-3","article-title":"Vectors for P-mediated transformation in Drosophila","volume-title":"Vectors: A Survey of Molecular Cloning Vectors and Their Uses","author":"Pirrotta","year":"1988"},{"key":"2022011809362536800_R48","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/35618","article-title":"Evidence for evolutionary conservation of sex-determining genes","volume":"391","author":"Raymond","year":"1998","journal-title":"Nature"},{"key":"2022011809362536800_R49","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1101\/gad.5.11.2071","article-title":"Regulation of doublesex pre-mRNA processing occurs by 3\u2032-splice site activation","volume":"5","author":"Ryner","year":"1991","journal-title":"Genes Dev."},{"key":"2022011809362536800_R50","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0092-8674(00)81802-4","article-title":"Control of male sexual behavior and sexual orientation in Drosophila by the fruitless gene","volume":"87","author":"Ryner","year":"1996","journal-title":"Cell"},{"key":"2022011809362536800_R51","doi-asserted-by":"crossref","first-page":"8429","DOI":"10.1073\/pnas.83.21.8429","article-title":"Sexual mimicry regulates the attractiveness of mated Drosophila melanogaster females","volume":"83","author":"Scott","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2022011809362536800_R52","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1111\/j.1558-5646.1996.tb03945.x","article-title":"Reply to: female mate discrimination or male responses to female stimulation?","volume":"50","author":"Scott","year":"1996","journal-title":"Evolution"},{"key":"2022011809362536800_R53","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/genetics\/132.1.179","article-title":"Differentiation of a male-specific muscle in Drosophila melanogaster does not require the sex-determining genes doublesex or intersex","volume":"132","author":"Taylor","year":"1992","journal-title":"Genetics"},{"key":"2022011809362536800_R54","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1242\/dev.114.3.625","article-title":"Commitment of abdominal neuroblasts in Drosophila to a male or female fate is dependent on genes of the sex-determining hierarchy","volume":"114","author":"Taylor","year":"1992","journal-title":"Development"},{"key":"2022011809362536800_R55","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/dvg.1020150309","article-title":"Behavioral and neurobiological implications of sex-determining factors in Drosophila","volume":"15","author":"Taylor","year":"1994","journal-title":"Dev. Genet."},{"key":"2022011809362536800_R56","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1101\/gad.8.14.1703","article-title":"A splicing enhancer exhibits both constitutive and regulated activities","volume":"8","author":"Tian","year":"1994","journal-title":"Genes Dev."},{"key":"2022011809362536800_R57","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1093\/genetics\/123.3.535","article-title":"Regulation of behavioral and pheromonal aspects of sex determination in Drosophila melanogaster by the Sex-lethal gene","volume":"123","author":"Tompkins","year":"1989","journal-title":"Genetics"},{"key":"2022011809362536800_R58","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/genetics\/143.1.331","article-title":"Courtship anomalies caused by doublesex mutations in Drosophila melanogaster","volume":"143","author":"Villella","year":"1996","journal-title":"Genetics"},{"key":"2022011809362536800_R59","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/bies.950170113","article-title":"Moving up the hierarchy: a hypothesis on the evolution of a genetic sex determination pathway","volume":"17","author":"Wilkins","year":"1995","journal-title":"Bioessays"},{"key":"2022011809362536800_R60","doi-asserted-by":"crossref","first-page":"5525","DOI":"10.1073\/pnas.92.12.5525","article-title":"Misexpression of the white (w) gene triggers male-male courtship in Drosophila","volume":"92","author":"Zhang","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/152\/4\/1653\/42227920\/genetics1653.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/152\/4\/1653\/42227920\/genetics1653.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T10:16:31Z","timestamp":1642500991000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/152\/4\/1653\/6047785"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,8,1]]},"references-count":60,"journal-issue":{"issue":"4","published-online":{"date-parts":[[1999,8,1]]},"published-print":{"date-parts":[[1999,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/genetics\/152.4.1653","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[1999,8,1]]},"published":{"date-parts":[[1999,8,1]]}}}