Four Theories on the Mechanisms of Sexual Differentiation

There are four theories on the mechanisms of sexual differentiation. The first theory advances that genes from the sex chromosome are the principal determining elements of sexual differentiation. According to the second theory, the Y chromosome possesses male-biasing properties causing males to be different from females. The third theory posits that the X chromosome amount determines differences in sex. Finally, the presence of autonomous sex-specific elements including the related pathway interactions is responsible for sex differences, according to the fourth theory (Arnold 5-7). This paper discusses how genes such as SRY and Wnt4 inhibit sexual differentiation of the opposite sex while promoting the development of specific reproductive structures.

SRY has been known to initiate the gonadal sexual differentiation. This gene encoded from the Y chromosome has been reported to start gonad differentiation towards male by inducing hormones in the gonads to shift in masculine compared to feminine which leads to important distinction in structural roles. According to Koopman (255), relatively undifferentiated gonadal tissues are induced by SRY to decide to develop into a testis. On the other hand, in the absence of SRY in females, ovarian development is initiated by sex or non-sex genes. This makes Sry the origin of sexual inequality that results in gonadal sexual differentiation.

SRY is a sequence-specific DNA-binding factor which is responsible for initiating the transcription of an associated Sox9 gene. To activate the transcription of Sox9, SRY binds to an enhancer sequence toward the 5′ end of the coding strand of the gene, leading to the synthesis of the protein SOX9, another sequence-specific DNA-binding factor. A function of SOX9 is binding the abovementioned enhancer located toward the 5′ end of the coding strand of Sox9 which enhances SOX9 expression, thus, creating a positive feedback loop. This feedback loop makes sure uninterrupted SOX9 protein production, thereby locking in the male gonad formation pathway. This protein is also capable of increasing the transcription of multiple genes required for testis phenotype, indicating the pivotal function of this protein in male gonad development (Koopman 252).

According to DiNapoli and Capel (5), in the bipotential gonad, there is a precarious balance between two developmental pathways. On one side is the male-promoting pathway involving SOX9 and FGF9, or fibroblast growth factor 9. Opposite this is the female-promoting pathway involving WNT4 (Wingless-Type MMTV Integration Site Family, Member 4) and RSPO1 (Roof plate-specific Spondin 1). SRY tips this equilibrium of antagonism between Fgf and Wnt towards testis development by increasing suppression of Sox9. The mere presence of SRY strengthens the SOX9 and FGF9 positive feedback which outcompetes the female WNT4 and RSPO1 signals, resulting in testis differentiation. Without SRY, the female-promoting signals stop the male feedback loop, resulting in ovarian differentiation.

WNT4 is an integral regulator of human and mice gonadal differentiation and has a pivotal role during the early stages of embryogenesis. WNT4, which encodes a cysteine-rich protein secreted to affect several developmental changes, is under the family of WNT genes. The proteins encoded from these genes bind to cell-surface proteins of the members of the fizzled family. WNT4 is particularly important in the formation of the urogenital system. It has been noted that lack of Wnt4 leads to masculinization while its over-expression in the forming male gonad disrupts this male gonadal formation and reduces synthesis of male hormone. It has been demonstrated that non-sex expression of Wnt is critical during regulation of development of feminine germ cells. This gene has been reported to maintain germ cell cysts as well as follicular gene expression in during the initial phase of formation. Furthermore, Wnt4 has also been reported to provide E-cadherin and beta-catenin female pattern expression (Biason-Lauber 2).

The function Wnt4 during the formation of ovary is inhibition of the translocation mesophrenos to the gonad of endothelial and steroidogenic cells, indicating the involvement of Wnt4 in cell migration during gonad development’s early stages. Lack of the of the protein in the gonad of females, on the other hand, leads to an increase in ectopic coelomic blood vessel as well as an increase in testis domain allocated to vascular formation (Jeays-Ward et al. 438).

Wnt4 has also been reported to regulate Dax1 which is known to antagonize SRY function in gonad development. In the WNT pathway, Dax1 expression is potentially initiated through beta-catenin which is an integral protein involved in signal-transduction in the said cascade. Together with Dax1, Fst which stands for Follistatin and TGF-b superfamily binding protein control vascular borders as well as regulates survival of ovarian germ line. And as already mentioned, Wnt4 and FGF9 also serve as antagonistic signals in ovary and testis differentiation (Yu et al. 2).

These observations have promoted the idea that Wnt4 serve both as an anti-male gonad gene as well as an element factor in the formation of testis. During the formation of the male gonad cords and while testicular cell types are being decided, WNT4 is down-regulated to suppress subsequent development of testis. On the other hand, WNT4 expression remains strong inside the ovary which is consistent with the mechanisms of testicular development inhibition to promote ovarian differentiation at a later time (Yu et al. 6).

In conclusion, sexual differentiation is a delicate equilibrium between the two sexual pathways involving multiple genes as well as their encoded proteins. Sry and Wnt4 are two of these genes that work antagonistically with corresponding genes in opposite pathways and sometimes cooperatively to decide the fate of the gonad. These two genes do not act exclusively but are involved in the downstream expression of other sexual determination or sexual differentiation genes such as Sox9 and Dax1. These mechanisms confirm the presence of autonomous sex-deciding elements as well as associated subsequent pathway interactions that are responsible for sexual differentiation.