Differentiation of Gonad
18.2.1 Differentiation of Sex in Domestic and Wild Mammals
The basic mechanism of sex determination is common in all mammals. It depends on the quantitative relationship between male and female-determining genes and their interface within the embryo.
The females and males have XX and XY karyotypes, respectively. Hence, it was believed that the sex-determining factor was the presence of two X chromosomes for many decades. But, in the nineteenth century, it was proved that the determinant of maleness and femaleness was under the influence of the Y chromosome and the specific region of the Y chromosome that determines maleness was identified. The development of male gonads is triggered by the ‘testis-determining factor’ (TDF) encoded on the short arm of the Y chromosome. There are three candidates under TDF: H-Y antigen, zinc finger Y (ZFY) gene and ‘sex-determining region on the chromosome Y’-gene or sry gene. The H-Y antigen is present only in males and classified as a minor histocompatibility antigen. The ZFY gene helps in spermatogenesis. The third candidate of TDF is sry gene which encodes a transcription factor that initiated the testes forming pathway at the medullary region of the developing bipotent gonad at the 7th week of embryonic life in humans. The testis starts producing two hormones during its development, namely testosterone and anti- Mullerian hormone (AMH). Testosterone and its metabolites (5α-dihydrotestosterone, 5α-DHT) promote the formation of accessory organs of the male reproductive system, whereas AMH regresses the Mullerian duct. It also stimulates Leydig cells to produce testosterone under the influence of placental human chorionic gonadotropin at about the 8th week of gestation.Fig. 18.1 Developmentof gonads in male and female from a bipotent foetus. [The sexually undifferentiated gonads (middle) comprising of both the male (Wolffian duct) and the female (Mullerian duct) gonads.
The Wolffian duct leads to the development of male reproductive system (left), and the Mullerian duct leads to female reproductive system (right)]
The accessory sex organs of males are developed from the mesonephric duct under the influence of testosterone. The epididymis is developed from the proximal part of the mesonephric duct and connects with the rete testis via residual mesonephric tubules. The vas deferens is developed from the distal mesonephric duct. The seminal vesicle is developed as a diverticulum at the terminal portion of the epididymis. The testosterone stimulates the epithelium at the region of the prostatic urethra to form the ducts and stroma of the prostate gland. The bulbourethral glands are developed as an outward invagination from the anterior urethra.
The regression of mesonephros allows the testes to float free in the peritoneal cavity like with mesentery. From the caudal pole of the testes, a mesodermal band called gubernaculum originates and passes toward the inguinal region through the posterior abdominal wall. A peritoneal pouch named the processus vaginalis appears before the gubernaculum at the 6th month of gestation. This pouch develops into tunica vaginalis and holds the testes suspended after its descent around the 8th month of gestation.
The sry gene’s counterpart in females for ovary determination is yet to be identified, and it was postulated that the development of the ovary is a default process. Recently, the ‘Z’ theory for ovarian determination has been proposed. The ‘Z’ factor, present in the XX karyotype, promotes ovarian development and suppresses testicular development. There are different candidate genes under the Z factor (ovarydetermining genes). Dax1 (dosage-sensitive sex-reversal- adrenal hypoplasia congenital-critical region of the X chromosome gene1) was initially proposed as an ovarydetermining gene due to its ovary-specific expression pattern, but later, it was found that Dax1 is not essential for ovarian development; rather, it has roles in testicular development.
So, it was eliminated from ovarian determining factors. Wnt4, an ovarian specific gene, was reported to inhibit testis determining pathway and promote ovarian development. The most potential candidate of the Z factor is Foxl2, a transcription factor that plays a crucial role in normal ovarian development. Another candidate gene of Z factor, namely R-spondin family, member 1 (RSPO1), encodes a signalling molecule to regulate the WNT signalling pathway and promotes ovarian development. It also antagonizes testes formation. Under the influence of Z factor genes, the cortex of the ridge is activated and the Mullerian (paramesonephric) or female reproductive duct is developed as an invagination of the surface epithelium of the mesonephros (Fig. 18.1). The Mullerian ducts thus formed extend in cranial-caudal fashion and fuse at the caudal end to form a Y-shaped structure called uterovaginal primordium from which the uterus, the cervix, and the upper portion of the vagina are developed. Uterine development is initiated around the 8th week of gestation, and vaginal development continues until the 20th week in humans. Estrogenic receptor in the vaginal epithelium hasTable 18.1 The key regulatory mammalian sexual development genes
| Name of the genes | Major regulation/ activity |
| Wt1, Sf1, Lhx9, Emx2, L33 | Development of bipotent gonad |
| Gata4/Fog2, Sry, Sox9, Sox8, Fgf9, Dax1, Pod1, Dhh, Pgdra, Pgds, Arx, Artx, Insl3, Lgr8, Hoxa10, Hoxa11, Amh, Misrl1, Pax2, Lim1, Dmrt1 | Testis-determining pathway |
| Wnt4, FoxL2, Dax1, RSPO1 | Ovary-determining pathway |
been found during the 21st week. The fallopian tubes are developed from the unfused portions of Mullerian ducts. The caudal most uterovaginal primordium fuses the urogenital sinus to form the vagina and hymen.
The key regulatory mammalian sexual development genes and their probable roles in sex determination have been presented in Table 18.1 and Fig. 18.2.
18.2.2 Differentiation of Sex in Bird
In contrast to mammals, the males are homogametic (ZZ), and females are heterogametic (ZW) in birds. The avian species lack sry gene; instead, the testes determining factor for birds is Z chromosome-specific double-sex and Mab-3 related transcription factor #1(DMRT1). Another gene, namely, SOX9, is responsible for Sertoli cell differentiation. The ovary-determining factor of birds is two W-linked genes, avian sex-specific W-linked (ASW) and Female-Expressed Transcript 1 (FET1). Other ovary-determining factors like HINTW, FOXL2, WNT4 and RSPO1 are also present in W-chromosome. The avian embryos bearing ZZ chromosomes have a higher quantity, and a higher expression level of DMRT1 triggers testicular development. In females, a lower level of DMRT1 is insufficient to repress ovarian development genes, thus favouring ovarian development. The left gonad becomes an ovary with thickened cortex and vacuolated medulla during ovarian development, but the right one is regressed.
18.3