Unveiling the roles of Sertoli cells lineage differentiation in reproductive development and disorders: a review

Abstract

In mammals, gonadal somatic cell lineage differentiation determines the development of the bipotential gonad into either the ovary or testis. Sertoli cells, the only somatic cells in the spermatogenic tubules, support spermatogenesis during gonadal development. During embryonic Sertoli cell lineage differentiation, relevant genes, including WT1, GATA4, SRY, SOX9, AMH, PTGDS, SF1, and DMRT1, are expressed at specific times and in specific locations to ensure the correct differentiation of the embryo toward the male phenotype. The dysregulated development of Sertoli cells leads to gonadal malformations and male fertility disorders. Nevertheless, the molecular pathways underlying the embryonic origin of Sertoli cells remain elusive. By reviewing recent advances in research on embryonic Sertoli cell genesis and its key regulators, this review provides novel insights into sex determination in male mammals as well as the molecular mechanisms underlying the genealogical differentiation of Sertoli cells in the male reproductive ridge.

Keywords: Sertoli cell; embryonic cell development; mice; primordial germ cell; sex determination; spermatogenesis.

Figure 1

Regulatory mechanisms of cytokines in male sex determination in mice. SRY, the only sex-determining gene located on the Y chromosome, binds to GATA4 in a MAPK-dependent manner to facilitate its own on-time expression and cooperates with SF1 to promote SOX9 expression. Activated SOX9 induces SRY expression and forms a positive feedback pathway with WT1 and DMRT1 to promote further SOX9 expression. SOX9 promotes the expression of testis development-associated factors, including FGF9, AMH, SOX8, PTGDS, and PGD2, facilitating embryonic development into a male phenotype. MAPK, mitogen-activated protein kinase; SOX9, sex-determining region Y-box 9; AMH, anti-Müllerian hormone; DMRT1, doublesex and mab-3 related transcription factor 1; FGF9, fibroblast growth factor 9; GATA4, GATA binding protein 4; PGD2, prostaglandin D2; PTGDS, prostaglandin D synthase; SF1, steroidogenic factor-1; SRY, sex-determining region Y; WT1, Wilms’ tumor 1.

Figure 2

Regulatory mechanisms of WT1 in sex differentiation. (A) In fetal WT1 ⁺ somatic cells, WT1 inhibits their differentiation into Leydig cells by activating the Notch pathway. In Sertoli cells, WT1 persists and promotes the lineage differentiation of Sertoli cells by inhibiting SF1 and activating the non-canonical Wnt pathway. (B) In Sertoli cells, WT1 activates WNT4, which activates two non-canonical Wnt pathways. In the Wnt/PCP signaling pathway, phosphorylated DVL activates Rac and Rho; Rac1 activates JNK; and RHO activates the related helix protein ROCK. JNK and ROCK then work together to regulate cell polarity. In the Wnt/Ca⁺ signaling pathway, Ca²⁺ activates PKC, which further stimulates CDC42 and promotes actin polymerization, thereby affecting cell polarity. WT1 promotes the expression of its target gene, WID, which forms a complex with DVL to inhibit WNT3a expression and, thus, β-catenin signaling. However, whether this mechanism exists in Sertoli cells remains to be confirmed. WT1, Wilms’ tumor 1; DVL, phosphorylated Disheveled.

Figure 3

Regulatory mechanisms of SF1 in sex differentiation. SF1 directly binds TES, which synergistically activates TESCO with SRY, leading to a rapid upregulation of SOX9. SF1 then binds to TES along with SOX9 to maintain SOX9 expression in Sertoli cells. SF1 activates the AMH promoter in vivo and inhibits the production of Müllerian tubules, and COUP-TFII and SF1 synergistically activate the INSL3 promoter, which promotes spermatogonial cell development and maturation. TES, testis-specific enhancer of SOX9; TESCO, testicular enhancer core; SF1, steroidogenic factor-1; SOX9, sex-determining region Y-box 9.

Figure 4

Regulatory mechanisms of SOX9 in sex differentiation. SOX9 can maintain SOX9 expression in Sertoli cells through three pathways mediated by SF1, FGF9/FGFR2, and PGTDS/PGD2. SRY upregulates SOX9 expression in undifferentiated gonads by binding to TES. SOX9 upregulates FGF9 and forms a positive feed-forward loop with FGF9 to maintain SOX9 expression. SOX9 promotes the expression of PTGDS in vivo by binding to the PTGDS promoter. The persistence of SOX9 promotes the production of L-PGDS, which leads to the accumulation of PGD2 and thus activates the transcription of SOX9. Later, these SOX9 ⁺ pre-Sertoli cells will form the primitive cords with spermatogenic cells. SOX9, sex-determining region Y-box 9; SRY, sex-determining region Y; FGF9, fibroblast growth factor 9; FGFR2, fibroblast growth factor receptor 2.

Figure 5

Graphical summary During sex determination in the male embryo, the expression of numerous cytokines at specific times and spaces act together to regulate the lineage differentiation of Sertoli cells. GATA4 ensures the transition of PGCs to meiotic germ cells by promoting the formation of germinal ridges. WT1 influences the polarity of Sertoli cells through the regulation of the non-canonical WNT pathway, which promotes the lineage differentiation of Sertoli cells. SF1 participates in mammalian sex determination through the activation of the promoter of AMH. SOX9 maintains its expression in Sertoli cells through three pathways mediated by SF1, FGF9/FGFR2, and PGDS/PGD2, respectively, thus ensuring that a sufficient number of Sertoli cells are available to induce testicular development. GATA4, GATA binding protein 4; PGCs, primordial germ cells; SF1, steroidogenic factor-1; AMH, anti-Müllerian hormone; SOX9, sex-determining region Y-box 9; FGF9, fibroblast growth factor 9; PGD2, prostaglandin D2; PTGDS, prostaglandin D synthase.