For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
11
views
50
references
 Top references
cited by
35
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      184
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Sex determination and maintenance: the role of DMRT1 and FOXL2

      review-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In many species, including mammals, sex determination is genetically based. The sex chromosomes that individuals carry determine sex identity. Although the genetic base of phenotypic sex is determined at the moment of fertilization, the development of testes or ovaries in the bipotential early gonads takes place during embryogenesis. During development, sex determination depends upon very few critical genes. When one of these key genes functions inappropriately, sex reversal may happen. Consequently, an individual's sex phenotype may not necessarily be consistent with the sex chromosomes that are present. For some time, it has been assumed that once the fetal choice is made between male and female in mammals, the gonadal sex identity of an individual remains stable. However, recent studies in mice have provided evidence that it is possible for the gonadal sex phenotype to be switched even in adulthood. These studies have shown that two key genes, doublesex and mad-3 related transcription factor 1 ( Dmrt1) and forkhead box L2 ( Foxl2), function in a Yin and Yang relationship to maintain the fates of testes or ovaries in adult mammals, and that mutations in either gene might have a dramatic effect on gonadal phenotype. Thus, adult gonad maintenance in addition to fetal sex determination may both be important for the fertility.

          Related collections

          Most cited references50

          • Record: found
          • Abstract: found
          • Article: not found

          Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.

          Ryohei Sekido, Robin Lovell-Badge (2008)
          The mammalian Y chromosome acts as a dominant male determinant as a result of the action of a single gene, Sry, whose role in sex determination is to initiate testis rather than ovary development from early bipotential gonads. It does so by triggering the differentiation of Sertoli cells from supporting cell precursors, which would otherwise give follicle cells. The related autosomal gene Sox9 is also known from loss-of-function mutations in mice and humans to be essential for Sertoli cell differentiation; moreover, its abnormal expression in an XX gonad can lead to male development in the absence of Sry. These genetic data, together with the finding that Sox9 is upregulated in Sertoli cell precursors just after SRY expression begins, has led to the proposal that Sox9 could be directly regulated by SRY. However, the mechanism by which SRY action might affect Sox9 expression was not understood. Here we show that SRY binds to multiple elements within a Sox9 gonad-specific enhancer in mice, and that it does so along with steroidogenic factor 1 (SF1, encoded by the gene Nr5a1 (Sf1)), an orphan nuclear receptor. Mutation, co-transfection and sex-reversal studies all point to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate Sox9 and then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Our results open up the field, permitting further characterization of the molecular mechanisms regulating sex determination and how they have evolved, as well as how they fail in cases of sex reversal.
          Article 0 comments Cited 239 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.

            N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag … (2009)
            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.
            Article 0 comments Cited 230 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              DMRT1 prevents female reprogramming in the postnatal mammalian testis

              Clinton K. Matson, Mark W Murphy, Aaron Sarver … (2011)
              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 .
              Article 0 comments Cited 172 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Asian J Androl
                Journal ID (iso-abbrev): Asian J. Androl
                Journal ID (publisher-id): AJA
                Title: Asian Journal of Andrology
                Publisher: Medknow Publications & Media Pvt Ltd (India )
                ISSN (Print): 1008-682X
                ISSN (Electronic): 1745-7262
                Publication date (Print): Nov-Dec 2017
                Publication date (Electronic): 13 January 2017
                Volume: 19
                Issue: 6
                Pages: 619-624
                Affiliations
                [1 ]Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
                [2 ]Department of Pediatric, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
                Author notes
                Correspondence: Dr. L Ye ( yeleping@ 123456163.com ) or Dr. H Chen ( hchen13@ 123456jhu.edu )
                Article
                Publisher ID: AJA-19-619
                DOI: 10.4103/1008-682X.194420
                PMC ID: 5676419
                PubMed ID: 28091399
                SO-VID: 48b46102-c737-4022-8d63-814e5acdd5ee
                Copyright © Copyright: © The Author(s)(2017)
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                Date received : 09 April 2016
                Date revision received : 02 July 2016
                Date accepted : 14 November 2016
                Categories
                Subject: Review

                Keywords: dmrt1,foxl2,sex determination,sex maintenance
                Data availability:
                Keywords: dmrt1, foxl2, sex determination, sex maintenance

                Comments

                Comment on this article

                scite_

                Similar content184

                See all similar

                Cited by35

                See all cited by

                Most referenced authors769

                See all reference authors