When do the gonads become active

But Henriette Uhlenhaut from the European Molecular Biology Laboratory has found that this story is woefully incomplete. Uhlenhaut developed a strain of genetically engineered mice, whose copies of FOXL2 could be deleted with the drug tamoxifen.

The change was a thorough one; the altered organs were testes right down to the structure of their cells and their portfolio of active genes. They developed testosterone-secreting Leydig cells, which pumped out as much of the hormone as their counterparts in XY mice. They only fell short of actually producing sperm.

The two genes are at opposite ends of a tug-of-war, with sex as the prize. Without its repressive hand, Sox9 switches on and sets about its gender-bending antics. FOXL2 also has a partner-in-repression — the oestrogen receptor, a docking molecule for the hormone oestrogen. The two proteins interact with one another and they cooperate to block Sox9. In these animals, oestrogens often cause males to change sex into females, and falling levels of oestrogen can trigger the reverse transformation.

FOXL2 may also be involved. The fact that oestrogen helps to maintain the gender of mice is surprising. Unlike other back-boned animals, mammals are thought to be largely insensitive to levels of sex hormones outside of development. The paired Mullerian duct migrate caudally along with Wolffian duct to reach urogenital sinus. It is a critical step in female reproductive tract development. If Mullerian ducts fail to merge with urogenital sinus, it can lead to lower vaginal agenesis. Sometimes it causes uterine and vaginal agenesis in females, which in turn leads to primary amenorrhea in girls MRKH syndrome.

In females, Mullerian ducts develop into fallopian tubes at their cranial end and fuse in midline to form the uterus and upper aspect of the vagina at their caudal ends. In a male fetus, during the 3rd month of fetal development, the Sertoli cells of the testes begin to secrete a substance called anti-Mullerian hormone.

WDs play a significant role in the fetus, and it induces the formation of three kidney primordial, namely pronephros, mesonephros, and metanephros. Initially, WD drains the first kidney or pronephros and subsequently functions as the excretory duct of the mesonephros. After the development of a definitive kidney, it acquires reproductive function. The part of the mesonephric duct just below this, elongate and convoluted to form epididymis and the remainder of the duct gradually develops a thick muscular coat and forms the vas deferens.

Seminal vesicles develop from the caudal end of each mesonephric duct as a lateral diverticulum. A part of the mesonephric duct, between seminal vesicle and urethra, becomes a common ejaculatory duct. During the 9th and 10th weeks of embryonic life, SRY induced Leydig cell differentiation occurs, which leads to testosterone production. Testosterones plays an important role in the stabilization of the mesonephric duct. Locally produced testosterone from the testis is essential for virilization of Wolffian duct, and they act directly to virilize it, not their derivatives.

The absence of testosterone in females leads to a regression of the Wolffian duct. External genitalia in male and female are ambisexual initially, then it undergoes sex differentiation and leads to the formation of male and female forms of external genitalia.

Up to the 9th week, the urogenital and the external genitalia are identical in both the sexes. In the 5th week, mesenchymal cells migrate to the perineum as cloacal folds. These mesenchymal cells assemble in the midline and form genital tubercle. The genital tubercle is located just above the urogenital ostium, and it is covered laterally by urogenital folds and labioscrotal folds.

Epithelial cells from urogenital sinus invade genital tubercle results in the formation of the epithelial urethral plate. These stages are identical in both male and female fetuses, and it occurs between the gestational age of 8 and 12 weeks. In males, the genital tubercle undergoes growth and elongation under the influence of testicular androgens and form penis—the scrotum forms by the fusion of labioscrotal folds at the midline.

The solid epithelial plate undergoes canalization and forms a groove on the surface of the genital tubercle, which is bounded by urethral folds. Penile urethra is formed by the fusion of urethral folds in the midline, thus converting groove into the penile urethra. Failure of this fusion results in hypospadias abnormal urethral opening at the tip of the penis proximal to its original location.

The penile foreskin forms from the nearby ectoderm. The development of male external genitalia complete by 14 weeks of gestation. But the testes start to descend from the abdominal cavity only at ten weeks of gestation. The descend is aided by gubernaculum, which is a fold of peritoneum and is attached to the testes. The descent of testes is completed by the 25th to 35th weeks.

Those with undescended testes have an increased chance of getting testicular tumors, especially germ cell tumors. Dihydrotestosterone, which forms from the testosterone with the help of 5-alpha reductase induces the differentiation of male external genitalia and development of urogenital sinus.

Female external genitalia development is regulated by the absence of androgens and maternal estrogens. The caudal end of the fused paramesonephric ducts come in contact with the posterior part of the urogenital sinus, where the sinovaginal bulb develops, and it will form the lower two-thirds of the vagina. Initially, it was solid and lumen forms later. Hymen separates the vagina and the remaining part of the urogenital sinus.

In the absence of testosterone, the genital tubercle forms the clitoris. The urethral folds and labioscrotal folds fail to fuse and become labia minora and majora. The differentiation of female external genitalia starts by 11 weeks and completes by 20 weeks of gestation. When a child is born, it requires careful examination for the symmetry of external genitalia, pigmentation of the genitals, presence of palpable gonads, and labioscrotal fusion.

The genital labioscrotal swellings fuse and the anogenital distance increases. At crown-rump length 90 mm 12 th weeks the penile urethra is formed. The growth of the genital tubercle continues during gestation. The differentiation of the urogenital sinus and the external genitalia depends on the presence of the fetal testicle. In its absence, whether ovaries are present or not, the vagina develops and the labioscrotal swellings do not fuse.

Testosterone is the hormone responsible for the male differentiation of the urogenital sinus and the external genitalia. However the presence of the 5a-reductase is necessary as the active metabolite on the external genitalia is dihydrotestosterone 46, The enzyme has been detected in these organs prior to their masculinization.

Testosterone acts directly on the differentiation of the epididymis, the vas deferens and the seminal vesicle. Reduction of testosterone to dihydrotestosterone by 5a-reductase is necessary to obtain differentiation of the prostate, the prostatic utricule, the scrotum and the penis Fig.

High dose of estrogens administrated in the pregnant animal may cause abnormal development of the male genitalia, leading to an intersex condition. Such anomalies have been described in human male neonates whose mothers have received diethylstilbestrol during pregnancy The concept proposed by Jost of an asymmetrical sex differentiation remains nowadays valid.

These factors and hormones act on target cells and tissues only during a " critical " period of development. The mechanism of this chronological " critical " period still lacks to date an adequate biological explanation. Edited by Aldo Campana,. Sizonenko Division of Biology of Growth and Reproduction, Department of Pediatrics, University Cantonal Hospital, Geneva 14, Switzerland Fetal sexual differentiation is a very complicated series of events actively programmed, at appropriate critical periods of fetal life, which involves both genetic and hormonal factors leading to the sexual dimorphism observed at birth Table 1.

Genetic sex The critical role of the Y chromosome and of male hormones in male orientation is well documented, the development of the female sexual differentiation occurring in the absence of male genetic determinants.

Gonadal differentiation The undifferentiated gonadal primordium, which is located at the ventral surface of the primitive kidney or mesonephros, is already visible in the 5 mm human embryo and consists of a thickening of the coelomic epithelium. Testicular differentiation The differentiation of the gonadal ridge into a testis is a rapid phenomenon, which contrasts with the slow and late development of the ovary. Ovarian differentiation Orientation of the primordial gonad towards ovarian differentiation in XX subjects appears after the 2 nd month of fetal age.

Hormonal factors Hormones secreted by the fetal differentiated gonads induce the development of the internal and external genitalia. Fetal testis Fetal Leydig cells produce testosterone in high amounts. Fetal ovary Fetal ovary is able to convert androgens to estrogens in vitro Wolffian ducts Wolffian ducts are present in the embryo at a crown-rump length of mm, and serve as the excreting duct to the mesonephros. Differentiation of the urogenital sinus and the external genitalia In both sexes the urogenital and the external genitalia are similar up to the 9 th week crown-rump length 30 mm.

Conclusions The concept proposed by Jost of an asymmetrical sex differentiation remains nowadays valid. References Baker, T. Bidlingmaier, F. Blanchard, M. G, and Josso, N. Byskov, A. Cate, R. Cell Genet. Clements, J. Donahoe, P. Elger, W. Fentener van Vlissingen, F. Ferguson-Smith, M.

Ford, C. Overzier, pp. Academic Press, London. Forest, M. Francavilla, S. Gartler, S. Harris and K. Hirschkorn, pp. Plenum Press, New York. George, F. Gubbay, J. Held, K. Ranke, and R. Rosenfeld, pp.

PLoS Genet. Jeays-Ward, K. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Karl, J. Three-dimensional structure of the developing mouse genital ridge. B Biol. Sertoli cells of the mouse testis originate from the coelomic epithelium. Kent, J. A male-specific role for SOX9 in vertebrate sex determination. PubMed Abstract Google Scholar. Kim, Y. Balancing the bipotential gonad between alternative organ fates: a new perspective on an old problem.

Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. Kirby, J. Google Scholar. Klattig, J. WT1-mediated gene regulation in early urogenital ridge development.

Lambeth, L. Transgenic chickens overexpressing aromatase have high estrogen levels but maintain a predominantly male phenotype. Endocrinology , 83— Lawrence, M. Functional transport of organic anions and cations in the murine mesonephros.

Renal Physiol. Liew, W. Polygenic sex determination system in zebrafish. Lin, Y. Numb regulates somatic cell lineage commitment during early gonadogenesis in mice. Liu, C. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells.

Mapping lineage progression of somatic progenitor cells in the mouse fetal testis. Loffler, K. Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved, early-acting gene in vertebrate ovarian development. Maatouk, D. Stabilization of beta-catenin in XY gonads causes male-to-female sex-reversal. Major, A. FOXL2 antagonises the male developmental pathway in embryonic chicken gonads. Martineau, J. Male-specific cell migration into the developing gonad.

Matsuda, M. McCarrey, J. Chick gonad differentiation following excision of primordial germ cells. McLaren, A. Somatic and germ-cell sex in mammals. Merchant-Larios, H. Environmental sex determination mechanisms in reptiles. Mesonephric stromal cells differentiate into leydig cells in the mouse fetal testis.

Cell Res. Early morphogenesis of chick gonad in the absence of mesonephros. Growth Differ. Mork, L. Temporal differences in granulosa cell specification in the ovary reflect distinct follicle fates in mice. Nef, S. Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Characterizing the bipotential mammalian gonad. Nicol, B. Gonadal identity in the absence of pro-testis factor SOX9 and pro-ovary factor beta-catenin in mice.

Building an ovary: insights into establishment of somatic cell lineages in the mouse. Nishikimi, H. Nishino, K. Characterization of mesonephric cells that migrate into the XY gonad during testis differentiation. Niu, W. Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary. Piprek, R. Piprek Cham: Springer International Publishing , 1— Pott, S.

Single-cell ATAC-seq: strength in numbers. Genome Biol. Rastetter, R. Marker genes identify three somatic cell types in the fetal mouse ovary. Rebourcet, D. Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis. Ricci, G. Rotem, A. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Schmahl, J. Cell proliferation is necessary for the determination of male fate in the gonad.

Sry induces cell proliferation in the mouse gonad. Development , 65— Sekido, R. Mechanisms of gonadal morphogenesis are not conserved between chick and mouse. Shima, Y. Fetal Leydig cells dedifferentiate and serve as adult Leydig stem cells. Siegfried, K. Germ line control of female sex determination in zebrafish. Slanchev, K.

Development without germ cells: the role of the germ line in zebrafish sex differentiation. Smith, C. Male-specific cell migration into the developing gonad is a conserved process involving PDGF signalling.

Cloning and expression of R-Spondin1 in different vertebrates suggests a conserved role in ovarian development. BMC Dev. Stevant, I. Dissecting cell lineage specification and sex fate determination in gonadal somatic cells using single-cell transcriptomics.

Single cell transcriptome sequencing: A new approach for the study of mammalian sex determination. Genetic control of gonadal sex determination and development.

Trends Genet. Deciphering cell lineage specification during male sex determination with single-Cell RNA sequencing. Svingen, T. Building the mammalian testis: origins, differentiation, and assembly of the component cell populations.