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Our knowledge on sex differentiation in mammals has considerably progressed during the last decennials, beginning with the discovery of the testis-determining factor. Here, the morphogenetic processes involved in the early gonadic switch will be presented, together with the major genes involved in testis and ovary formation. Existing differences between the widely used mouse model and other mammals, such as human and goat, will be highlighted.

The genetic mechanism controlling sexual differentiation had remained unknown for a long time. Karyotype analysis of sex-inverted patients or individuals with ambiguous sexual differentiation has enabled the localization and identification of genes involved. It is currently known that the SRY gene is responsible for the initiation of a cascade reaction leading to male differentiation of the primitive gonad. SRY is a +/- 820 base pairs gene located on the small arm of the Y chromosome, more precisely within the 1A1 alpha sub-segment. Although a few other genes are known to be involved in the downstream regulation of SRY, their precise mode of action is yet unknown.

The aim of this review is to underscore the major role of forkhead proteins in the adult ovary. Indeed, they revolutionize the idea of terminal differentiation of adult tissues with for example the in vivo reprogrammation of an adult organism on the one hand, and, on the other hand, the therapeutic possibilities of fertility preservation in women. In mammals, SRY, a transcription factor encoded by the Y chromosome, is responsible for the development of the undifferentiated gonads into testes. However, testis differentiation can occur in its absence. The studies of M. Treier demonstrate that FOXL2 is required to maintain the ovarian phenotype. Indeed, the absence of Foxl2 in an adult mouse ovary leads to an up regulation of testis-specific genes and a transformation of granulosa and theca cells into Sertoli-like and Leydig-like cells. The maintenance of the ovarian phenotype is an active process throughout life. Although multiple follicles are present in mammalian ovaries, most of them remain dormant. During reproductive life, some follicles are activated for development. There is an inefficient activation of dormant follicles within cryopreserved ovaries. An inhibition of the FOXO3a pathway in the mouse ovary leads to an enhancement of the activation of the dormant follicles. After transplantation, there are more preovulatory stage follicles and, after fertilization and embryo transfer, they lead to a healthy progeny. In human ovarian cortical fragments, the same inhibition and a xenotransplantation permit a development of more primordial follicles to the preovulatory stage. Thus, this treatment may be a hope to treat infertile women with cryopreserved ovaries or with a diminishing ovarian reserve.

Testis determination is the complex process by which the bipotential gonad becomes a normal testis during embryo development. As a consequence, this process leads to sexual differentiation corresponding to the masculinization of both genital track and external genitalia. The whole phenomenon is under genetic control and is particularly driven by the presence of the Y chromosome and by the SRY gene, which acts as the key initiator of the early steps of testis determination. However, many other autosomal genes, present in both males and females, are expressed during testis formation in a gene activation pathway, which is far to be totally elucidated. All these genes act in a dosage-sensitive manner by which quantitative gene abnormalities, due to chromosomal deletions, duplications or mosaicism, may lead to testis determination failure and sex reversal.

The various processes involved in sexual differentiation have been considerably clarified over the last few years through advances in biochemistry and molecular genetics. The cloning of the gene responsible for testicular determination SRY, of the anti-Müllerian hormone and anti-Müllerian hormone receptor genes, of the several steroidogenic enzymes genes, of the 5 alpha-reductase type 2 gene and of the androgen receptor gene has permitted to elucidate the molecular defects causing abnormal sexual differentiation. These data have brought a substantial impact on the understanding of human male sexual differentiation and its main disorders.