The road to maleness: from testis to Wolffian duct

Abstract

The establishment of the male internal reproductive system involves two crucial events: the formation of the testis and the maintenance and differentiation of the Wolffian duct. Testis formation, particularly the specification of Sertoli cell and Leydig cell lineages, is controlled strictly by genetic components initiated by the testis-determining gene SRY (sex-determining region of the Y chromosome). Conversely, Wolffian duct differentiation is not directly mediated via the composition of the sex chromosome or SRY; instead, it relies on androgens derived from the Leydig cells. Leydig cells do not express SRY, indicating that a crosstalk must be present between the SRY-positive Sertoli and Leydig cells to ensure normal androgen production. Recent advancement of genetic and genomic approaches has unveiled the molecular pathways for differentiation of Sertoli cells and Leydig cells as well as development of the Wolffian duct.

Figure 1

Molecular and cellular pathways that connect Sertoli cells, Leydig cells and Wolffian duct development based on mouse genetic models. Solid lines represent pathways supported by genetic or biochemical evidence. Dotted lines represent putative pathways responsible for the corresponding events. At the time of sex determination in mouse embryos (E10.5–11.5), Sry is expressed in pre-Sertoli cells (light blue cell; only one is shown here). SRY, along with other transcription regulators (DAX1, FOG2, GATA4, SF1 and other, unidentified factors), upregulates the expression of Sox9, which putatively controls the production of AMH, DHH, PDGFs and prostaglandin D synthetase (PGDS). PGDS leads to the production of PGD2, which recruits Sry-negative Sertoli cell precursors by inducing Sox9 expression. DHH and PDGFs derived from the Sertoli cells act as paracrine factors to induce specification and differentiation of fetal Leydig cells (yellow cells; only one is shown here). The developing fetal Leydig cells then produce androgens and INSL3. Androgens facilitate the survival and differentiation of the Wolffian duct and male external genitalia. INSL3, along with androgens, ensure the occurrence of testis descent.