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JOE-19-0277.Pdf 243 3 Journal of A T Major, K L Ayers et al. FOXL2 suppresses male gonad 243:3 211–228 Endocrinology development RESEARCH FOXL2 antagonises the male developmental pathway in embryonic chicken gonads Andrew T Major1*, Katie L Ayers2*, Justin Chue2, Kelly N Roeszler2, and Craig A Smith1 1Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia 2Murdoch Childrens Research Institute, Royal Children’s Hospital and University of Melbourne Departments of Paediatrics, Royal Children’s Hospital, Parkville, Victoria, Australia Correspondence should be addressed to C A Smith: [email protected] *(A Major and K Ayers contributed equally to this work) Abstract FOXL2 is a conserved transcription factor with a central role in ovarian development Key Words: and function. Studies in humans and mice indicate that the main role of FOXL2 is in the f FOXL2 postnatal ovary, namely folliculogenesis. To shed light on the function and evolution f embryonic gonad of FOXL2 in the female gonad, we examined its role in embryonic avian gonads, using f chicken in ovo overexpression and knockdown. FOXL2 mRNA and protein are expressed f sex determination female specifically in the embryonic chicken gonad, just prior to the onset of sexual f sexual differentiation differentiation. FOXL2 is expressed in the medullary cord cells, in the same cell type f ovary as aromatase (CYP19A1). In addition, later in development, expression also becomes f testis localised in a subset of cortical cells, distinct from those expressing oestrogen receptor alpha. Misexpression of FOXL2 in the male chicken embryonic gonad suppresses the testis developmental pathway, abolishing local expression of the male pathway genes SOX9, DMRT1 and AMH and repressing Sertoli cell development. Conversely, knockdown of FOXL2 expression allows ectopic activation of SOX9 in female gonads. However, misexpression of FOXL2 alone was insufficient to activate aromatase expression in male gonads, while FOXL2 knockdown did not affect aromatase expression in females. These results indicate that FOXL2 plays an important role in embryonic differentiation of the avian ovary via antagonism of SOX9, but may be dispensable for aromatase activation at embryonic stages. The data suggest that FOXL2 has different roles in different species, Journal of Endocrinology more central for embryonic ovarian differentiation in egg-laying vertebrates. (2019) 243, 211–228 Introduction The forkhead box (FOX) family of transcription factors are helix’ (a helix-turn-helix core, flanked by two loops, or conserved developmental regulators, playing diverse roles ‘wings’) (Clark et al. 1993, Katoh & Katoh 2004). Fox in cell differentiation, apoptosis and tumorigenesis (Brunet proteins diverge in sequence outside the forkhead domain. et al. 1999, Schmidt et al. 2002, Stahl et al. 2002, Lehmann They typically act as transcriptional activators, but can et al. 2003, Krupczak-Hollis et al. 2004, Senokuchi et al. also act as repressors, and they often act in partnerships 2008, Ahn et al. 2015, Eelen et al. 2016, Deng et al. 2017). with co-factors (Uhlenhaut & Treier 2006, Rosario et al. FOX proteins share a conserved 110 amino acid DNA- 2012). There are currently 19 recognised FOX subfamilies, binding domain, the forkhead box, a so-called ‘winged designated A to S. One FOX gene, FOXL2, plays a central https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-19-0277 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/07/2021 05:26:28AM via free access -19-0277 Journal of A T Major, K L Ayers et al. FOXL2 suppresses male gonad 243:3 212 Endocrinology development role in female reproductive function in vertebrates (Baron tumours (Beysen et al. 2004, Shah et al. 2009). Hence, in et al. 2005, Bertho et al. 2016). Its expression in mammals both mouse and human, FOXL2 has a key role in ovarian is restricted to the ovary, eyelids and pituitary gland. In the maintenance after birth, but may not itself be required pituitary, FOXL2 is required for transcription of follicle- for embryonic ovarian differentiation. One of its key roles stimulating hormone (FSH) (Ellsworth et al. 2006, Corpuz is the regulation of gonadal steroidogenesis (Baron et al. et al. 2010, Tran et al. 2013). FOXL2 also plays a key role 2004, Pisarska et al. 2004, Pannetier et al. 2006, Uhlenhaut in the ovary, where it is expressed in follicular (granulosa) & Treier 2006). cells (Cocquet et al. 2002, Uhlenhaut & Treier 2006, The exact role of Foxl2 during ovarian development Auguste et al. 2011). In the mouse, Foxl2 is required for appears to differ among vertebrate species. As noted above, postnatal granulosa cell development and maintenance. FOXL2 is required postnatally in mouse and human, that Although Foxl2 is expressed during embryonic stages, is, after embryonic differentiation of the ovary. In goats, homozygous null mutant mice exhibit ovarian failure the FOXL2 gene is located 300 kb downstream of a critical that only becomes apparent postnatally. Foxl2−/− mice 11.7 kb genomic region that is deleted and causes XX have impaired follicle formation characterised by sex reversal associated with the Polled (hornless) intersex granulosa cell dysfunction, extensive follicular atresia and phenotype (Pailhoux et al. 2001). FOXL2 is expressed sterility (Schmidt et al. 2004, Uda et al. 2004). The testis in XX foetal goat gonads and targeted deletion of the marker Sox9 also becomes expressed in Foxl2−/− gonads gene using zinc-finger nucleases leads to female-to-male postnatally (Ottolenghi et al. 2005). However, loss of sex reversal (Pailhoux et al. 2002, Boulanger et al. 2014). function can cause masculinisation during embryonic Embryonic XX gonads develop as testes rather than stages when the feminising genes, Wnt4 or R-Spo1, are also ovaries. These observations identify FOXL2 as a key ovary- deleted (Ottolenghi et al. 2007, Auguste et al. 2011). In determining gene in goats, in contrast to its postnatal role such compound mutants, Sertoli cells develop and testis in mice and humans. Among fishes, the Foxl2 gene is also markers such as Sox9 and Dmrt1 are expressed. Ectopic expressed in an ovarian-specific manner in tilapia and expression of Foxl2 in foetal mouse testes can cause partial targeted deletion also causes female-to-male sex reversal sex reversal (at E14.5 and postnatally) (Nicol et al. 2018). (Li et al. 2013, Zhang et al. 2017). Taken together the data indicate that Foxl2 does not play In the mammalian ovary, one of the direct targets of a central functional role in sexual differentiation of the FOXL2 is considered to be CYP19A1, which encodes the gonads in mouse, but is more important in maintaining rate-limiting enzyme involved in oestrogen synthesis, granulosa cell identity postnatally. Aromatase (Pannetier et al. 2006, Fleming et al. 2010). In mouse, Foxl2 is thought to be required to FOXL2 can bind and activate the CYP19A1 promoter maintain the ovarian phenotype throughout life by in mammals and in a fish, the Nile Tilapia Batista( et al. actively repressing the male (testis) pathway, probably 2007, Wang et al. 2007, Fleming et al. 2010, Rosario in conjunction with oestrogen (Ottolenghi et al. 2005, et al. 2012). The potential interaction between FOXL2 Garcia-Ortiz et al. 2009). Conditional loss of Foxl2 in adult and aromatase is especially noteworthy among non- mice can lead to ‘trans-differentiation’ of the gonad from mammalian vertebrates, because oestrogen synthesis plays ovary to testis, with granulosa cells losing females markers a decisive role in ovarian differentiation at embryonic and expressing Sertoli cell markers, such as Sox9. Under stages (Vaillant et al. 2001, Ramsey & Crews 2009, Barske these conditions, Foxl2 can act together with oestrogen & Capel 2010, Guiguen et al. 2010, Lambeth et al. 2013, receptor alpha to negatively regulate Sox9 (Uhlenhaut Zhang et al. 2017). In these vertebrates, Foxl2 has an et al. 2009). In humans, heterozygous mutations in early, conserved female-specific expression pattern in the FOXL2 cause blepharophimosis/ptosis/epicanthus embryonic gonads. This applies to all species that have inversus syndrome (BPES), which includes eyelid and been examined, from fishes to reptiles and birds Cocquet( mild craniofacial defects associated with frequent et al. 2003, Loffleret al. 2003, Rhen et al. 2007, Bertho et al. premature ovarian failure and infertility (Crisponi et al. 2016, Hirst et al. 2017, Zhang et al. 2017, Bertho et al. 2018). 2001, De Baere et al. 2001, Castro & Trujillo 2002). FOXL2 In the chicken embryo, FOXL2 is expressed in female but in humans is required for granulosa cell maintenance not male embryonic gonads (Loffleret al. 2003, Govoroun (Kim et al. 2011, Kuo et al. 2011). Furthermore, disruption et al. 2004, Hudson et al. 2005). Expression data in birds of FOXL2 can result in ovarian tumours (Benayoun and reptiles suggest that FOXL2 may activate CYP19A1 in et al. 2010). One missense mutation in FOXL2 (C134W) the gonad, as it does in mammals, but this has not been underlies over 90% of ovarian adult-type granulosa cell demonstrated. Elucidating the exact role of FOXL2 in avian https://joe.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JOE-19-0277 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/07/2021 05:26:28AM via free access Research Journal of A T Major, K L Ayers et al. FOXL2 suppresses male gonad 243:3 213 Endocrinology development gonadal development would be particularly useful. Firstly, was determined as described by Hamburger and Hamilton it would shed light on the evolution of FOXL2 function in (Hamburger & Hamilton 1992). All embryos were the vertebrate ovary. Secondly, the global poultry industry genetically sexed by PCR as described previously, using currently seeks methods of manipulating sex ratios (all genomic DNA obtained from limb tissue (Clinton et al. female chickens are required by the egg industry, and 2001).
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