WNT4, RSPO1, and FOXL2 in Sex Development

Anna Biason-Lauber

doi:10.1055/s-0032-1324722

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2012; 30(05): 387-395
DOI: 10.1055/s-0032-1324722

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

WNT4, RSPO1, and FOXL2 in Sex Development

Authors

Anna Biason-Lauber

¹Department of Medicine, University of Fribourg, Fribourg, Switzerland

Abstract

The idea that the female sexual development happens by default was born in the middle of the last century after Jost performed his innovative experiments to study the bases of differentiation of the reproductive tract and found that the female reproductive tract develops even in the absence of any gonad. The term default (passive) attributed to the whole female developmental pathway, therefore, established itself, even if it was not originally so intended. However, recent developments have demonstrated that ovarian development is an active process. Wingless type MMTV integration site family, member 4 (WNT4), one of a few factors with a demonstrated function in the ovarian-determination pathway, has been found to be involved in sexual differentiation by suppressing male sexual differentiation, promoting Müllerian duct differentiation, and maintaining oocyte health. WNT4 expression in the ovary seems to be regulated by R-spondin 1 (RSPO1), a thrombospondin family member protein. The role and interactions of WNT4, RSPO1, and other factors such as forkhead transcription factor 2 in ovarian development and function will be discussed.

Keywords

ovarian differentiation - WNT4 - RSPO1

Full Text

References

References
1 McElreavey K, Vilain E, Abbas N, Herskowitz I, Fellous M. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci USA 1993; 90 (8) 3368-3372
2 He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development 2004; 131 (8) 1663-1677
3 Nusse R. Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface. Development 2003; 130 (22) 5297-5305
4 Pandur P, Läsche M, Eisenberg LM, Kühl M. Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis. Nature 2002; 418 (6898) 636-641
5 Jääskeläinen M, Prunskaite-Hyyryläinen R, Naillat F , et al. WNT4 is expressed in human fetal and adult ovaries and its signaling contributes to ovarian cell survival. Mol Cell Endocrinol 2010; 317 (1–2) 106-111
6 Jordan BK, Mohammed M, Ching ST , et al. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans. Am J Hum Genet 2001; 68 (5) 1102-1109
7 Vainio S, Heikkilä M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature 1999; 397 (6718) 405-409
8 Yao HH, Matzuk MM, Jorgez CJ , et al. Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis. Dev Dyn 2004; 230 (2) 210-215
9 Merchant H. Rat gonadal and ovarioan organogenesis with and without germ cells. An ultrastructural study. Dev Biol 1975; 44 (1) 1-21
10 McLaren A. Meiosis and differentiation of mouse germ cells. Symp Soc Exp Biol 1984; 38: 7-23
11 Naillat F, Prunskaite-Hyyryläinen R, Pietilä I , et al. Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Hum Mol Genet 2010; 19 (8) 1539-1550
12 Ottolenghi C, Pelosi E, Tran J , et al. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet 2007; 16 (23) 2795-2804
13 Mandel H, Shemer R, Borochowitz ZU , et al. SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am J Hum Genet 2008; 82 (1) 39-47
14 Domenice S, Corrêa RV, Costa EM , et al. Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients. Braz J Med Biol Res 2004; 37 (1) 145-150
15 Biason-Lauber A, Konrad D, Navratil F, Schoenle EJA. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004; 351 (8) 792-798
16 Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency—a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Hum Reprod 2007; 22 (1) 224-229
17 Philibert P, Biason-Lauber A, Rouzier R , et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab 2008; 93 (3) 895-900
18 Philibert P, Biason-Lauber A, Gueorguieva I , et al. Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Küster-Hauser syndrome). Fertil Steril 2011; 95 (8) 2683-2686
19 Kamata T, Katsube K, Michikawa M, Yamada M, Takada S, Mizusawa H. R-spondin, a novel gene with thrombospondin type 1 domain, was expressed in the dorsal neural tube and affected in Wnts mutants. Biochim Biophys Acta 2004; 1676 (1) 51-62
20 Kim KA, Kakitani M, Zhao J , et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 2005; 309 (5738) 1256-1259
21 Chassot AA, Gregoire EP, Magliano M, Lavery R, Chaboissier MC. Genetics of ovarian differentiation: Rspo1, a major player. Sex Dev 2008; 2 (4–5) 219-227
22 Chassot AA, Ranc F, Gregoire EP , et al. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet 2008; 17 (9) 1264-1277
23 Parma P, Radi O, Vidal V , et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet 2006; 38 (11) 1304-1309
24 Tomaselli S, Megiorni F, De Bernardo C , et al. Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Hum Mutat 2008; 29 (2) 220-226
25 Crisponi L, Deiana M, Loi A , et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001; 27 (2) 159-166
26 Cocquet J, Pailhoux E, Jaubert F , et al. Evolution and expression of FOXL2. J Med Genet 2002; 39 (12) 916-921
27 Pisarska MD, Bae J, Klein C, Hsueh AJ. Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology 2004; 145 (7) 3424-3433
28 Pannetier M, Fabre S, Batista F , et al. FOXL2 activates P450 aromatase gene transcription: towards a better characterization of the early steps of mammalian ovarian development. J Mol Endocrinol 2006; 36 (3) 399-413
29 Ellsworth BS, Egashira N, Haller JL , et al. FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Mol Endocrinol 2006; 20 (11) 2796-2805
30 Pannetier M, Renault L, Jolivet G, Cotinot C, Pailhoux E. Ovarian-specific expression of a new gene regulated by the goat PIS region and transcribed by a FOXL2 bidirectional promoter. Genomics 2005; 85 (6) 715-726
31 Moumné L, Batista F, Benayoun BA , et al. The mutations and potential targets of the forkhead transcription factor FOXL2. Mol Cell Endocrinol 2008; 282 (1–2) 2-11
32 Henderson ST, Johnson TE. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 2001; 11 (24) 1975-1980
33 Batista F, Vaiman D, Dausset J, Fellous M, Veitia RA. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proc Natl Acad Sci U S A 2007; 104 (9) 3330-3335
34 Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol 1996; 62: 167-215
35 Uhlenhaut NH, Jakob S, Anlag K , et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 2009; 139 (6) 1130-1142
36 Shah SP, Köbel M, Senz J , et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009; 360 (26) 2719-2729
37 Moumné L, Fellous M, Veitia RA. Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation. Hum Mol Genet 2005; 14 (23) 3557-3564
38 Moumné L, Dipietromaria A, Batista F , et al. Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum Mol Genet 2008; 17 (7) 1010-1019
39 Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA. Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. Hum Mol Genet 2009; 18 (17) 3324-3333
40 Benayoun BA, Georges AB, L'Hôte D , et al. Transcription factor FOXL2 protects granulosa cells from stress and delays cell cycle: role of its regulation by the SIRT1 deacetylase. Hum Mol Genet 2011; 20 (9) 1673-1686
41 Liang L, Soyal SM, Dean J. FIGalpha, a germ cell specific transcription factor involved in the coordinate expression of the zona pellucida genes. Development 1997; 124 (24) 4939-4947
42 Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science 2004; 305 (5687) 1157-1159
43 Soyal SM, Amleh A, Dean J. FIGalpha, a germ cell-specific transcription factor required for ovarian follicle formation. Development 2000; 127 (21) 4645-4654
44 De La Chesnaye E, Kerr B, Paredes A, Merchant-Larios H, Méndez JP, Ojeda SR. Fbxw15/Fbxo12J is an F-box protein-encoding gene selectively expressed in oocytes of the mouse ovary. Biol Reprod 2008; 78 (4) 714-725
45 Su YQ, Sugiura K, Wigglesworth K , et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development 2008; 135 (1) 111-121
46 Di Pasquale E, Rossetti R, Marozzi A , et al. Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab 2006; 91 (5) 1976-1979
47 Dixit H, Rao LK, Padmalatha VV , et al. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet 2006; 119 (4) 408-415
48 Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet 2007; 81 (3) 576-581
49 Palmer JS, Zhao ZZ, Hoekstra C , et al. Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. J Clin Endocrinol Metab 2006; 91 (11) 4713-4716
50 Chand AL, Ponnampalam AP, Harris SE, Winship IM, Shelling AN. Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. Fertil Steril 2006; 86 (4) 1009-1012
51 Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE, Carson SA. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril 2007; 87 (1) 143-146
52 Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod 2002; 8 (8) 729-733
53 Britt KL, Findlay JK. Regulation of the phenotype of ovarian somatic cells by estrogen. Mol Cell Endocrinol 2003; 202 (1–2) 11-17
54 Couse JF, Hewitt SC, Bunch DO , et al. Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science 1999; 286 (5448) 2328-2331
55 Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127 (19) 4277-4291
56 Lin L, Achermann JC. Steroidogenic factor-1 (SF-1, Ad4BP, NR5A1) and disorders of testis development. Sex Dev 2008; 2 (4–5) 200-209
57 Hanley NA, Ball SG, Clement-Jones M , et al. Expression of steroidogenic factor 1 and Wilms' tumour 1 during early human gonadal development and sex determination. Mech Dev 1999; 87 (1–2) 175-180
58 Murayama C, Miyazaki H, Miyamoto A, Shimizu T. Involvement of Ad4BP/SF-1, DAX-1, and COUP-TFII transcription factor on steroid production and luteinization in ovarian theca cells. Mol Cell Biochem 2008; 314 (1–2) 51-58
59 Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 2000; 67 (6) 1563-1568
60 Lourenço D, Brauner R, Lin L , et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 2009; 360 (12) 1200-1210
61 Jeays-Ward K, Hoyle C, Brennan J , et al. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development 2003; 130 (16) 3663-3670
62 Kocer A, Reichmann J, Best D, Adams IR. Germ cell sex determination in mammals. Mol Hum Reprod 2009; 15 (4) 205-213
63 Combes AN, Spiller CM, Harley VR , et al. Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation. Int J Dev Biol 2010; 54 (4) 683-689
64 Tomizuka K, Horikoshi K, Kitada R , et al. R-spondin1 plays an essential role in ovarian development through positively regulating Wnt-4 signaling. Hum Mol Genet 2008; 17 (9) 1278-1291