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WNT4 and Sex Development Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2008 WNT4 and sex development Biason-Lauber, A ; Konrad, D Abstract: Although factors involved in male sexual differentiation have been well studied, the pathways regulating female sexual differentiation remain incompletely defined. To date, no genes have been identi- fied to play a similar role in ovarian development as was shown for the SRY or SOX9 genes intesticular development. In mice, Wnt4 regulates the development of the female reproductive tract, antagonizes the production of testosterone, and is important for oocyte development. The recent demonstration of heterozygous WNT4 defects in patients with Mullerian agenesis and signs of ovarian hyperandrogenism added WNT4 to the growing list of genes such as SRY, SOX9, WT1, DAX1, and SF-1 contributing to human sexual development. In particular, WNT4 was the first human gene to be identified to direct development of the bipotential gonad towards ovaries. From a more clinical point of view, it seems that the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathog- nomonic signs of WNT4 defects, suggesting that WNT4 deficiency might be a clinical entity distinct from the typical Mayer-Rokitansky-Kuster-Hauser syndrome. DOI: https://doi.org/10.1159/000152037 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-5508 Journal Article Published Version Originally published at: Biason-Lauber, A; Konrad, D (2008). WNT4 and sex development. Sexual Development, 2(4-5):210-218. DOI: https://doi.org/10.1159/000152037 Review Article Sex Dev 2008;2:210–218 Received: May 06, 2008 DOI: 10.1159/000152037 Accepted: June 25, 2008 WNT4 and Sex Development A. Biason-Lauber D. Konrad University Children’s Hospital, Zurich , Switzerland Key Words Physiology of Sex Development ؒ Meyer-Rokitansky-Kuster-Hauser ؒ Müllerian ducts Ovarian development ؒ Syndrome hyperandrogenism ؒ Among all definitions of sexual differentiation, we like WNT the one from Wikipedia the best: ‘Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote (fer- Abstract tilized egg). As male and female individuals develop from Although factors involved in male sexual differentiation zygotes into fetuses, into infants, children, adolescents, have been well studied, the pathways regulating female sex- and eventually into adults, sex and gender differences at ual differentiation remain incompletely defined. To date, no many levels develop: genes, chromosomes, gonads, hor- genes have been identified to play a similar role in ovarian mones, anatomy, psyche, and social behaviors’ . In sex de- development as was shown for the SRY or SOX9 genes in tes- velopment we can distinguish two different processes: ticular development. In mice, Wnt4 regulates the develop- sex determination that is the developmental decision that ment of the female reproductive tract, antagonizes the directs the undifferentiated embryo into a sexually di- production of testosterone, and is important for oocyte de- morphic individual and sex differentiation that takes velopment. The recent demonstration of heterozygous place once the sex determination decision has been made WNT4 defects in patients with Müllerian agenesis and signs through factors produced by the gonads that determine of ovarian hyperandrogenism added WNT4 to the growing the development of the phenotypic sex. At the beginning list of genes such as SRY, SOX9, WT1, DAX1, and SF-1 contribut- of gestation (1st and 2nd week) embryos of the two sexes ing to human sexual development. In particular, WNT4 was differ only in their karyotypes. Starting at week 3, spe- the first human gene to be identified to direct development cific genes lead to the differentiation of the gonads which of the bipotential gonad towards ovaries. From a more clini- in turn produce hormones inducing anatomical and psy- cal point of view, it seems that the absence of a uterus (and chological differences and lead to behavioral differences not other Müllerian abnormalities) and the androgen excess that are ultimately influenced by the social environment. are the pathognomonic signs of WNT4 defects, suggesting The main steps of intrauterine sex differentiation are de- that WNT4 deficiency might be a clinical entity distinct from picted in figure 1 . At gestational weeks 6–7 the parame- the typical Mayer-Rokitansky-Kuster-Hauser syndrome. sonephric duct (Müllerian duct) develops next to the me- Copyright © 2008 S. Karger AG, Basel sonephric duct. If testes develop and secrete testosterone, © 2008 S. Karger AG, Basel Anna Biason-Lauber, MD 1661–5425/08/0025–0210$24.50/0 University Children’s Hospital Fax +41 61 306 12 34 Div. of Endocrinology/Diabetology E-Mail [email protected] Accessible online at: Steinwiesstrasse 75, CH-8032 Zurich (Switzerland) www.karger.com www.karger.com/sxd Tel. + 41 44 266 7623, Fax + 41 44 266 7169, E-Mail [email protected] Downloaded by: Universität Zürich, Zentralbibliothek Zürich 130.60.47.22 - 7/7/2016 10:05:31 AM 0 GW Paramesonephric Development of Wolffian ducts 4 Mesonephric (Müllerian) duct Migration of germ cells 5 Migration of germ cells (Wolffian) duct Testis 6 Development of Müllerian ducts Differentiation of seminiferous tubules 7 Ovary Regression of Müllerian ducts 8 Appearance of Leydig cells 9 1st meiotic prophase in oogonia Masculinization of external genitalia Wolffian ducts regression begins 10 Fetal testes in the internal inguinal rings Penile urethra completed 12–14 Appearance of first spermatogonia 14 Ductus 16 Appearance of first ovarian follicles deferens Urogenital Müllerian Max. Leydig cells. Testosterone peak 17 sinus tubercle Uterus Uterine Regression Leydig cells. Testosterone 20 Epididymal Prostatic lower tube duct utricle 1st multilayer ovarian follicles 24 Testis Canalisation of the vagina Efferent Urethra Ovary Cervix tubules Cessation of oogonia Descent of testes 28 multiplication Male Female 38 Fig. 1. Embryonic development. GW: Gestational week. Data de- Fig. 2. The undifferentiated sexual system at 6–7 weeks of gesta- rived from Bertrand et al. [1993]. tion. Precursor structures (top) and their mature counterparts (bottom) have the same color. From Stenchever and Goldfarb [1998]. the mesonephric (Wolffian) duct increases in size and Ovarian determining factors might help the process of differentiates into epididymis, vas deferens, and prostate. differentiation. However, these factors are yet to be deter- A glycoprotein secreted from the Sertoli cells, known as mined. The second model, called the Z-factor theory, was anti-Müllerian hormone (AMH) or Müllerian inhibiting proposed to explain the cases where XX individuals de- substance (MIS), results in Müllerian duct regression. If velop testes in the absence of SRY . According to this the- testes do not develop, the mesonephric duct does not ory, the XX gonad expresses a factor that has both anti- grow and eventually degenerates, whereas the parameso- testis and pro-ovary function. SRY in XY individuals acts nephric duct proliferates and the fallopian tube, uterus, as an inhibitor of the Z-factor to lift the block on the male and upper third of the vagina develop ( fig. 2 ). pathway. In this case, the bipotential gonad will differen- In mammals, including humans, the differentiation of tiate into a testis [McElreavey et al., 1993]. the gonads is the turning point of this whole process. The Although factors involved in male sexual differentia- classical textbook theory says that in the presence of the tion have been well studied ( fig. 3 ), the pathways regulat- sex determining region on the Y chromosome (SRY) , the ing female sexual differentiation remain incompletely default ovarian pathway of sex determination will be in- defined. To date, no genes have been identified to play a hibited and therefore testes will be formed. In the XX in- similar role in ovarian development as it was shown for dividual, due to the absence of SRY , no inhibition of the the SRY or SOX9 gene in testicular development. In mice, default program will take place and ovaries will develop. Wnt4, one of a few factors with a demonstrated function WNT4 and Sex Development Sex Dev 2008;2:210–218 211 Downloaded by: Universität Zürich, Zentralbibliothek Zürich 130.60.47.22 - 7/7/2016 10:05:31 AM Müllerian-duct-derived female reproductive tract WNT4 Steroidogenic enzymes HOXA9,10,11,13 Estrogen receptor Urogenital ridge Ovary Gastrulation Primitive streak Adrenal NOBOX Foxl2 BMP15 Fig␣ GDF9 Emx2, GATA-4, SF-1 WNT4 Fst DAX1 Lim1, Lhx9, WT1 M33 SRYSOX9 R-spondin1 Notochord DHH Gonad Intermediate DMRT1 mesoderm Kidney Testis Pax2 Steroidogenic enzymes Wolff-duct-derived male Androgen receptor reproductive tract AMH AMH receptor Fig. 3. Sexual differentiation cascade. Mutations in various genes gene encoding a protein that binds to a GATA DNA sequence; (bold) can lead to a variety of syndromes of dysgenesis involving HOXA: homeobox protein; Lhx9 : lim homeobox family member; the Müllerian or Wolffian ducts, gonads, kidneys, and adrenal Lim1 : homeobox gene important for limb development; M33: glands as a result of a deficiency or excess of the proteins shown. polycomb like protein, essential for male sexual differentiation in BMP15: bone morphogenic factor 15; DAX1 : dosage dependent mice; NOBOX: newborn ovary homeobox transcription factor; adrenal hypoplasia
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