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

睾丸间质细胞产生两种激素，胰岛素样3(INSL3)和睾酮(T)，这两种激素对于男性外生殖器、性附腺的正常发育、肌肉质量的增加以及成熟精子的产生是必不可少的。在哺乳动物中，至少有两种不同的间质细胞：胎儿间质细胞(FLC)和成年间质细胞(ALC)。FLC产生雄性激素和INSL3，使发育中的男性系统男性化。然而，由于这些细胞中的大多数在出生后不久就会萎缩，它们被认为不会对ALC群体做出贡献。ALC来源于未分化的前体细胞，人们认为这些细胞存在于胎儿时期，但在青春期之前才开始分化。第三个非常短暂的间质细胞群-新生儿间质细胞(NLC)-在灵长类动物中已被描述，但它们的来源和在其他物种中的存在尚不清楚。因此，间质细胞生物学的一个关键特征是，它们产生的激素来自不同的间质细胞群体，这些细胞在一生中的不同时间都处于活跃状态。我的研究计划的长期目标是研究这些不同的间质细胞群体是如何发展的，以及它们的激素产生是如何调节的。使用最先进的基因编辑技术，我们最近培育出了第一只特异性和强有力地针对Leydig细胞的转基因小鼠。这些新的小鼠品系将有助于我们提出的关于不同间质细胞群体的起源和潜在相互依赖的研究。我们的工作假设是，不同的间质细胞群体并不是独立的，而是有着密切而复杂的联系。我的研究计划的短期目标是确定FLC是否有助于其他间质细胞群的发育，Leydig干细胞是否存在于成年小鼠睾丸中，以及它们在受到侮辱(如暴露于内分泌干扰物)后是否能够重新填充Leydig细胞池。这一计划将为调节各种间质细胞群体的分化和相关性的基本机制提供新的见解。

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.