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Testicular Leydig cells induce masculinization of the whole body by producing androgens. It is well accepted that two distinct Leydig cell populations, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs), develop in the prenatal and postnatal stages, respectively. In case of mice, FLCs appear at around E12.5 and increase in number during fetal stages. The number of FLCs decreases after birth, and thereafter ALCs appear and increase in number rapidly during puberty. Although both FLCs and ALCs produce androgens, lineage relationship between FLCs and ALCs was unclear, and it remained an open question how two distinct Leydig cell populations sequentially differentiate in the testicular interstitium.
Ad4BP/SF-1 (Ad4-binding protein/Steroidogenic factor-1, officially NR5A1) is a nuclear receptor expressed in both FLCs and ALCs. We revealed that an upstream enhancer of Ad4BP/SF-1 gene has a potential to induce gene expression in FLCs but not ALCs. Therefore, we designated this enhancer as Fetal Leydig Enhancer (FLE) of Ad4BP/SF-1 gene. We performed lineage tracing of FLCs by using FLE and revealed that a part of FLCs dedifferentiate around birth and redifferentiate to ALCs at pubertal stage. Moreover, the dedifferentiated cells contribute to the peritubular myoid cells (PTMCs) and vascular pericytes (VPs) in the testicular interstitium. Although steroidgenic gene expression is completely absent in the PTMCs and VPs, they retained a potential to redifferentiate into ALCs at pubertal stage, suggesting that they serve as potential ALC stem cells. Given the functional importance of Ad4BP/SF-1 in Leydig cell differentiation, two distinct mouse models, FLC lineage specific Ad4BP/SF-1 gene disrupted mice and the mice lacking fetal Leydig enhancer (FLE) of Ad4BP/SF-1 gene, were generated. Both mouse lines demonstrated closely similar phenotypes; almost complete loss of FLCs, conspicuous decline or complete loss of ALCs, and massive interstitial fibrosis. These results support the conclusion that FLC and ALC sequentially arise from a single lineage, and FLE of Ad4BP/SF-1 gene is essential for not only initial FLC differentiation but also pubertal ALC redifferentiation.

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