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Genetic and Epigenetic Effects in Sex Determination Sezgin Ozgur Gunes1,2, Asli Metin Mahmutoglu1, and Ashok Agarwal*3

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Genetic and Epigenetic Effects in Sex Determination Sezgin Ozgur Gunes1,2, Asli Metin Mahmutoglu1, and Ashok Agarwal*3 Genetic and Epigenetic Effects in Sex Determination Sezgin Ozgur Gunes1,2, Asli Metin Mahmutoglu1, and Ashok Agarwal*3 Sex determination is a complex and dynamic process with multiple genetic cascade are not completely understood. This review aims at discussing and environmental causes, in which germ and somatic cells receive various current data on the genetic effects via genes and epigenetic mechanisms that sex-specific features. During the fifth week of fetal life, the bipotential affect the regulation of sex determination. embryonic gonad starts to develop in humans. In the bipotential gonadal tissue, certain cell groups start to differentiate to form the ovaries or testes. Birth Defects Research (Part C) 108:321–336, 2016. Despite considerable efforts and advances in identifying the mechanisms VC 2016 Wiley Periodicals, Inc. playing a role in sex determination and differentiation, the underlying mechanisms of the exact functions of many genes, gene–gene interactions, Key words: sex determination; SRY; SOXE; NR5A1; GATA4; WT1; epigenetics and epigenetic modifications that are involved in different stages of this Introduction formation via inducing a different set of genes (Sekido and Sex determination is a biological process determining the Lovell-Badge, 2008; Rigby and Kulathinal, 2015). development of the primordial gonad into male (testes) or Animal experiments and genetic analyses in patients female (ovary) gonads (Herpin and Schartl, 2011). During with developmental sex disorders (DSDs) have demonstrat- the sex determination cascade, the initial event is the forma- ed that many genes and pathways, such as GATA4, SOX9, tion of the gonadal primordium, also known as gonadal or NR5A1, FOG2, Hedgehog, and the Map Kinase signaling path- genital ridge (Ronfani and Bianchi, 2004). The gonadal pri- way, play critical roles in the sex determination process mordium derives from the mesonephros that is one of the (Cotinot et al., 2002). Recent studies have proposed that epi- tubular nephric structures of the urogenital ridges in mam- genetic mechanisms are also involved in the regulation of mals (Lucas-Herald and Bashamboo, 2014), and is coated by sex determination (Kuroki et al., 2013; Mulvey et al., 2014; coelomic epithelium (Wilhelm et al., 2013). Epithelial cells Skinner et al., 2015). In this review, current and past litera- derived from the proliferation of the epithelium of the ture on genetic effects on the regulation of sex determina- gonadal primordium enter the mesenchyme and result in tion, with special emphasis on male sex determination, is the formation of primitive sex cords. These sex cords lose discussed. In addition, the contribution of epigenetic mecha- nisms to the process of sex determination is reviewed. connections with the epithelial surface, share the same morphology in fetuses with XX or XY sex chromosomes, and SRY are called bipotential gonads (Matzuk and Lamb, 2008; Sex Determining Region Y (SRY) (OMIM *480000) is a single Sadler, 2011). exon gene and encodes a DNA binding protein, a member of A variety of genes including WT1, FOG2, and NR5A1 the high mobility group (HMG)-box family. The SRY gene enco- are known to play a role in the bipotential gonad forma- des a transcription factor and is located on the position p11.3 tion (Barrionuevo et al., 2012). The differentiation of bipo- of the Y-chromosome (Premi et al., 2006). This transcription tential gonads along the testis- or ovary-specific pathway factor is called the testis-determining factor (TDF), induces is induced by SRY gene expression (Wijchers and Festen- male sex determination, and has been proposed to play a piv- stein, 2011). The expression of the SRY gene gives rise to otal role in sex determination in males (Page et al., 1987). The the activation of downstream genes involved in testis for- SRY transcript has many transcription starting sites, with the mation by inducing Sertoli-cell differentiation, whereas the size of the transcript being approximately 900 nucleotides dysfunction or absence of SRY expression results in ovary (Clepet et al., 1993). The SRY protein is constituted of N- terminal, central, and C-terminal domains containing the HMG box which is an evolutionary conserved DNA binding 1 Department of Medical Biology, Faculty of Medicine, Ondokuz Mayis and bending domain spanning over 79 amino acids. The HMG University, Samsun, Turkey 2Department of Multidisciplinary Molecular Medicine, Ondokuz Mayis box motif provides binding to a specific DNA sequence via University, Health Science Institute, Samsun, Turkey interaction with the minor groove and causes bending of the 3American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, DNA helix up to a 908 angle. This bending enables the forma- Ohio tion of an active transcriptional complex on the DNA. Protein– *Correspondence to: Ashok Agarwal, Lerner College of Medicine, Andrology protein interactions and post-translational modifications also Center and the American Center for Reproductive Medicine, Cleveland take place in the HMG domain. Thus, since most of the muta- Clinic, Mail Code X-11, 10681 Carnegie Avenue, Cleveland, OH 44195. tions occur de novo in the DNA sequence encoding this E-mail: [email protected] domain, and these mutations cause to abnormalities in DNA Published online in Wiley Online Library (wileyonlinelibrary.com). Doi: 10.1002/bdrc. binding and sex reversal, the HMG box domain has a very crit- 21146 ical role (Helszer et al., 2013). HMG box domain mutations VC 2016 Wiley Periodicals, Inc. 322 MOLECULAR MECHANISMS IN SEX DETERMINATION also change nuclear importation and are involved in the pancreas specification, gliogenesis, and neural crest devel- minority of human sex reversal cases (Sim et al., 2008). opment (Huang et al., 2015). SOXE proteins contain the Alterations in the DNA sequence of the SRY gene can transcription activation domain, as well as the DNA- result in gonadal dysgenesis, which is one of the DSDs binding HMG domain, similar to all other SOX proteins. (Schlessinger et al., 2010). DSDs are congenital abnormities Moreover, the DNA-dependent dimerization domain is a with numerical or structural chromosomal aberrations, unique structure of SOXE proteins (Barrionuevo and gonadal, or anatomic sex development abnormalities (Ohne- Scherer, 2010). In mammals, SOXE genes are involved in sorg et al., 2014). 46,XX, 46,XY and sex chromosome DSDs sex determination (She and Yang, in press) via enhancing are categories of developmental sex disorders, according to the activities of testis-specific enhancer (TES) of Sox9 core the Chicago Consensus (Hughes et al., 2006). The aneuploi- element (TESCO) and anti-Mullerian Hormone (Amh)pro- dies of X- and/or Y-chromosomes cause sex chromosome moter (Otake and Kuroiwa, 2016). DSDs, including Turner syndrome (TS), Klinefelter syn- In 46,XY embryos, gonadal differentiation is initiated by drome (KS), and 45,X/46,XY mosaicism. Children with KS or SRY expression between 41 and 44 days postovulation TS have no genital differences in their early lives; whereas, (d.p.o.)/Carnegie stages 18 (CS18). Once SRY expression children with the mosaic 45,X/46,XY karyotype have ambig- peaks at 44 d.p.o./CS18, a period of time when sex cords are uous genitalia in their newborn period. Although 46,XX first seen, SOX9 gene activation is initiated in the bipotential DSDs and 46,XY DSDs result from different conditions, high gonad and triggers Sertoli cell differentiation. The expres- levels of androgen exposure during the fetal period and sion of the SRY gene continues up to 18-weeks gestation incomplete intrauterine virilization, respectively, they all (Hanley et al., 2000; Eggers et al., 2014). SOX9 gene expres- cause the generation of external genitalia improper to sex sion is promoted by not only SRY expression, but also chromosome constitution (Achermann et al., 2015). enhancers located in different regions upstream of SOX9 To date, more than 50 mutations of the SRY gene have gene, depending on tissue type and time (Lybaek et al., been associated with sex reversal (Andonova et al., 2015). 2014). TESCO is one of the regulatory elements of the SOX9 These mutations are summarized in Table 1. Most of the gene and engages an important role as an enhancer in sex mutations of SRY gene associated with gonadal dysgenesis determination of the mammalian organisms (Kimura et al., have been detected in the HMG box. Helszer et al. (2013) 2014). DNA lesions leading to changes in the upstream regu- detected a novel missense mutation (c.341A>G) causing the lation of SOX9 have been suggested to be related to SRY neg- substitution of asparagine by aspartic acid at codon 65 ative XX DSDs (Kojima et al., 2008). Benko et al. (2011) have (p.N65D) in the HMG box of SRY gene. The binding ability of reported duplications and deletions in the SOX9 regulatory the N65D variant of the SRY was analyzed by gel retardation region in patients with isolated 46,XX and 46,XY DSDs, analysis. These authors suggested that the c.341A>Gmuta- respectively. Although duplication in the upstream region of tion may also contribute to the pathogenesis of 46,XY gonadal SOX9 is known to cause SRY2 XX DSDs (Hyon et al., 2015), dysgenesis (Helszer et al., 2013). Although M64I is a classical polymorphisms of SOX9 do not result in SRY2 XX DSDs (Xia sex reversal mutation at position 9 in the HMG box, it has no et al., 2015). Recently, a study has proposed that the regula- adverse effect on DNA binding (McElreavey et al., 1992). tory regions of the SOX9 gene span two different regions, XY Another mutation with no effect on DNA binding activi- and XX sex reversal regions. Therefore, deletions or duplica- ty is the F108S mutation, a familial mutation in the SRY tions cause distinct forms of DSDs (Kim et al., 2015). gene (J€ager et al., 1992). More recently, the F108S mutation SOX9 has been found to be associated with elevated polyubiquiti- SOX9 (OMIM *608160) is an autosomal gene located on nation.
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