Mapping lineage progression of somatic progenitor cells in the mouse fetal testis

Testis morphogenesis is a highly orchestrated process involving lineage determination of male germ cells and somatic cell types including supporting (Sertoli cells) and interstitial cells (Leydig cells and others). While the origin and differentiation of germ cells are known, the developmental course specific for each somatic cell lineage has not been clearly defined. Here we construct a comprehensive map of somatic cell lineage progression in the mouse testis. Both supporting and interstitial cell lineages arise from WT1+ somatic progenitor pool in the gonadal primordium. A subpopulation of WT1+ progenitor cells acquire SOX9 expression and become Sertoli cells that form the testis cords, whereas the remaining WT1+ cells contribute to progenitor cells in the testis interstitium. Interstitial progenitor cells further diversify through the acquisition of HES1 expression, an indication of Notch activation, at the onset of sex determination. Once Sertoli cells differentiate they produce Hedgehog signals that induce GLI1 expression in the HES1+ interstitial progenitor cells. The interstitial cells eventually developed into two cell lineages: steroid-producing fetal Leydig cells and non-steroidogenic cells. The steroid-producing fetal Leydig cell population is restricted by Notch2 signaling from the neighboring somatic cells. The non-steroidogenic progenitor cells retain their undifferentiated state during fetal stage and give rise to adult Leydig cells in the post-pubertal testis. These results provide the first lineage progression map that illustrates the sequential establishment of supporting and interstitial cell populations in testis morphogenesis, and reveal the specific involvement of Notch2 in controlling steroid-producing fetal Leydig cell population.