Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

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Abstract

Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

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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.

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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.

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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 .

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 26 March 2020

Publication date Collection: April 2020

Volume: 21

Issue: 7

Electronic Location Identifier: 2282

Affiliations

[1 ]Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM/42) da Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, 05403 900 São Paulo, Brazil; nathalialisboa.endocrino@ 123456gmail.com

[2 ]Serviço de Endocrinologia da Santa Casa de Belo Horizonte, Av. Francisco Sales, 1111, 30150-221 Belo Horizonte, Minas Gerais, Brazil

[3 ]Department of Diabetes and Endocrinology, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, UK; tarini.chetty@ 123456nhslothian.scot.nhs.uk

[4 ]Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; anne.joergensen.02@ 123456regionh.dk

[5 ]International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Blegdamsvej 9, 2100 Copenhagen, Denmark

[6 ]Medical Research Council (MRC) Centre for Reproductive Health, The University of Edinburgh, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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[* ]Correspondence: rod.mitchell@ 123456ed.ac.uk

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Rod T Mitchell https://orcid.org/0000-0003-4650-3765

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Publisher ID: ijms-21-02282

DOI: 10.3390/ijms21072282

PMC ID: 7178030

PubMed ID: 32224856

SO-VID: 76a9329c-9d00-4971-a436-5c4f8975ae4d

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

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Most cited references 150

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

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

DMRT1 prevents female reprogramming in the postnatal mammalian testis

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