Probing the origins and crosstalk between the different Leydig cell populations in the mammalian gonad

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Testicular Leydig cells produce 2 hormones, insulin-like 3 (INSL3) and testosterone (T) that are indispensable for the proper development of external male genitalia, sex accessory glands, increased muscle mass, as well as production of mature sperm. In mammals, there are at least two distinct populations of Leydig cells: fetal Leydig cells (FLC) and adult Leydig cells (ALC). FLC produce androgens and INSL3 needed to masculinize the developing male system. However, since most of these cells atrophy shortly after birth, they are not thought to contribute to the ALC population. ALC derive from undifferentiated precursor cells that are believed to be present during fetal life but only start to differentiate prior to puberty. A third and very transient Leydig cell population-neonatal Leydig cells (NLC)-has been described in primates but their origin, and existence in other species remain unclear. Therefore, a key feature of Leydig cell biology is that the hormones they produce originate from distinct populations of Leydig cells that are active at different times throughout life. The long-term goal of my research program is to study how these different Leydig cell populations develop and how their hormone production is regulated. Using state-of-the-art gene editing technologies, we have recently generated the first transgenic mice that specifically and robustly target Leydig cells. These novel mouse lines will be instrumental for our proposed studies on the origin and potential interdependence of the different Leydig cell populations. Our working hypothesis is that the different Leydig cell populations are not independent but rather share close and complex ties. The short-term goal of my research program is to determine whether FLC contribute to the development of the other Leydig cell populations and whether Leydig stem cells reside in the adult mouse testis and whether they could repopulate the Leydig cell pool after an insult such as exposure to endocrine disruptors. This program will provide novel insights into the fundamental mechanisms regulating the differentiation and relatedness of the various Leydig cell populations.