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      DMRT1 prevents female reprogramming in the postnatal mammalian testis

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          Abstract

          Sex in mammals is determined in the foetal gonad by the presence or absence of the Y chromosome gene Sry, which controls whether bipotential precursor cells differentiate into testicular Sertoli cells or ovarian granulosa cells 1 . This pivotal decision in a single gonadal cell type ultimately controls sexual differentiation throughout the body. Sex determination can be viewed as a battle for primacy in the foetal gonad between a male regulatory gene network in which Sry activates Sox9 and a female network involving Wnt/β-catenin signaling ( Supplemental Fig. 1) 2 . In females the primary sex-determining decision is not final: loss of the FOXL2 transcription factor in adult granulosa cells can reprogramme granulosa cells into Sertoli cells 2 . Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor 3 in mouse Sertoli cells, even in adults, activates Foxl2 and reprogrammes Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced, and germ cells appear feminized. Thus Dmrt1 is essential to maintain mammalian testis determination, and competing regulatory networks maintain gonadal sex long after the foetal choice between male and female. Dmrt1 and Foxl2 are conserved throughout vertebrates 4, 5 and Dmrt1-related sexual regulators are conserved throughout metazoans 3 . Antagonism between Dmrt1 and Foxl2 for control of gonadal sex may therefore extend beyond mammals. Reprogramming due to loss of Dmrt1 also may help explain the etiology of human syndromes linked to DMRT1, including disorders of sexual differentiation 6 and testicular cancer 7 .

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          Most cited references23

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          DMY is a Y-specific DM-domain gene required for male development in the medaka fish.

          Although the sex-determining gene Sry has been identified in mammals, no comparable genes have been found in non-mammalian vertebrates. Here, we used recombinant breakpoint analysis to restrict the sex-determining region in medaka fish (Oryzias latipes) to a 530-kilobase (kb) stretch of the Y chromosome. Deletion analysis of the Y chromosome of a congenic XY female further shortened the region to 250 kb. Shotgun sequencing of this region predicted 27 genes. Three of these genes were expressed during sexual differentiation. However, only the DM-related PG17 was Y specific; we thus named it DMY. Two naturally occurring mutations establish DMY's critical role in male development. The first heritable mutant--a single insertion in exon 3 and the subsequent truncation of DMY--resulted in all XY female offspring. Similarly, the second XY mutant female showed reduced DMY expression with a high proportion of XY female offspring. During normal development, DMY is expressed only in somatic cells of XY gonads. These findings strongly suggest that the sex-specific DMY is required for testicular development and is a prime candidate for the medaka sex-determining gene.
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            Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.

            In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.
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              The avian Z-linked gene DMRT1 is required for male sex determination in the chicken.

              Sex in birds is chromosomally based, as in mammals, but the sex chromosomes are different and the mechanism of avian sex determination has been a long-standing mystery. In the chicken and all other birds, the homogametic sex is male (ZZ) and the heterogametic sex is female (ZW). Two hypotheses have been proposed for the mechanism of avian sex determination. The W (female) chromosome may carry a dominant-acting ovary determinant. Alternatively, the dosage of a Z-linked gene may mediate sex determination, two doses being required for male development (ZZ). A strong candidate avian sex-determinant under the dosage hypothesis is the conserved Z-linked gene, DMRT1 (doublesex and mab-3-related transcription factor 1). Here we used RNA interference (RNAi) to knock down DMRT1 in early chicken embryos. Reduction of DMRT1 protein expression in ovo leads to feminization of the embryonic gonads in genetically male (ZZ) embryos. Affected males show partial sex reversal, characterized by feminization of the gonads. The feminized left gonad shows female-like histology, disorganized testis cords and a decline in the testicular marker, SOX9. The ovarian marker, aromatase, is ectopically activated. The feminized right gonad shows a more variable loss of DMRT1 and ectopic aromatase activation, suggesting differential sensitivity to DMRT1 between left and right gonads. Germ cells also show a female pattern of distribution in the feminized male gonads. These results indicate that DMRT1 is required for testis determination in the chicken. Our data support the Z dosage hypothesis for avian sex determination.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                21 July 2011
                20 July 2011
                04 February 2012
                : 476
                : 7358
                : 101-104
                Affiliations
                [1 ]Developmental Biology Center and Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA
                [2 ]Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN, USA
                [3 ]University of Minnesota Masonic Cancer Center, Minneapolis, MN, USA
                [4 ]School of Molecular Biosciences, Washington State University, Pullman, WA, USA
                Author notes
                [* ]Corresponding author: zarko001@ 123456umn.edu , Phone: 612-625-9450
                Correspondence and requests for materials should be addressed to D.Z. ( zarko001@ 123456umn.edu ) or V.J.B. ( bardw001@ 123456umn.edu )
                Article
                nihpa313068
                10.1038/nature10239
                3150961
                21775990
                d01b271e-c7d4-4b6c-8d13-414b6ff26530

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Child Health & Human Development : NICHD
                Award ID: R01 HD010808-34 || HD
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