Cell fate commitment during mammalian sex determination

Abstract

The gonads form bilaterally as bipotential organs that can develop as testes or ovaries. All secondary sex characteristics that we associate with 'maleness' or 'femaleness' depend on whether testes or ovaries form. The fate of the gonads depends on a cell fate decision that occurs in a somatic cell referred to as the 'supporting cell lineage'. Once supporting cell progenitors commit to Sertoli (male) or granulosa (female) fate, they propagate this decision to the other cells within the organ. In this review, we will describe what is known about the bipotential state of somatic and germ cell lineages in the gonad and the transcriptional and antagonistic signaling networks that lead to commitment, propagation, and maintenance of testis or ovary fate.

Figure 1

Commitment to the male pathway involves the down-regulation of many genes associated with female development. Diagram depicting the change in the expression of each gene in the XX gonad (X-axis) and XY gonad (Y-axis) between E11.0 and E12.0. Both of these changes can contribute to sexually dimorphic expression. Line graphs show changes in expression of two representative male genes (Dhh and Sox9) and two representative female genes (Msx1 and Wnt4) in the XY (blue line) and XX (red line) gonads. Higher expression of the male pathway genes, Dhh and Sox9, occur primarily through up-regulation in the XY gonad. Sexually dimorphic expression of many of the genes in the female pathway, Msx1 and Wnt4, occurs through down-regulation in the XY gonad. Adapted from Munger SC et al. [11].

Figure 2

Commitment and maintenance of gonadal cell fate. In XX and XY gonads at the bipotential stage, supporting cell precursors are exposed to male and female promoting signals that antagonize each other. In the XY gonad, expression of Sry triggers up-regulation of Sox9 and Fgf9, which activate the male pathway and repress signals that promote the female pathway (WNT4/RSPO1 and β-catenin). Supporting cell precursors commit to Sertoli cell fate and orchestrate testis development by promoting Leydig cell differentiation from steroidogenic progenitors, and regulating mitotic arrest in germ cells. In the XX gonad, in the absence of Sry to initiate the male pathway, Wnt4 and Rspo1 maintain β-catenin signaling to promote the female pathway. Supporting cell precursors commit to granulosa cell fate and orchestrate ovary development by promoting Theca cell differentiation from steroidogenic progenitors, and regulating meiotic entry in germ cells. Reinforcing signals (dotted lines) exist between somatic and germ cells in the developing testis and ovary. In the adult testis, Dmrt1 is required for maintaining Sertoli cell fate by repressing female promoting signals, while in the adult ovary, abolishing female promoting signals leads to loss of granulosa cell fate and up-regulation of Sox9 and other markers of Sertoli fate.