Primordial germ cell differentiation and the initiation of testicular cancer

描述（由申请人提供）：睾丸生殖细胞肿瘤（TGCT）是儿童和年轻男性最常见的癌症。TGCT是由原始生殖细胞（PGC）发育异常引起的，原始生殖细胞是配子的胚胎前体。由于TGCT的遗传成分复杂且肿瘤在胚胎发生期间开始，因此在人类中已鉴定出很少涉及PGCs的肿瘤转化的因素。在129/Sv小鼠中，肿瘤在胚胎第13.5天（E13.5）左右开始，129/Sv小鼠是唯一具有明显自发性TGCT频率的近交系小鼠。在同一发育时期，发育性腺中的局部视黄酸（RA）水平影响生殖细胞减数分裂或有丝分裂停滞（有丝分裂：减数分裂开关）。在雌性胚胎性腺中，RA诱导Stra 8的表达，Stra 8在生殖细胞进入减数分裂所需的分化事件中发挥作用。在雄性胚胎性腺中，RA被降解，Stra 8表达未被诱导，并且生殖细胞（成年雄性生殖细胞的前体）保持静止直到出生后。将研究异常RA信号传导和Stra 8表达在雄性胚胎生殖细胞的过早分化和TGCT易感小鼠中肿瘤干细胞群体的建立中的作用。将使用体外和体内畸胎瘤形成试验、表达试验、功能丧失突变以及多能性和致瘤性试验的组合来表征三种特定目的。目的1：异常视黄酸信号是否有助于TGCT易感性以及胚胎生殖细胞如何暴露于RA？目的2 -Stra 8是否在胚胎生殖细胞分化和TGCT易感性中起作用？目的3 -胚胎生殖细胞的亚群是否具有TGCT干细胞的功能？这些测试将揭示生殖细胞生物学和TGCT肿瘤发生的独特方面，并可能为人类TGCT的诊断和治疗提供新的靶点。 公共卫生相关性：男性生殖细胞发育缺陷可导致睾丸生殖细胞肿瘤（TGCT）。TGCT是儿童和年轻男性中最常见的癌症。尽管在人类中进行了大量的工作，但对早期TGCT发育所涉及的细胞过程知之甚少。TGCT的小鼠模型将有助于指导未来在人类中的潜在研究，并为TGCT的识别和治疗提供更好的诊断标志物和靶标。

DESCRIPTION (provided by applicant): Testicular germ cell tumors (TGCTs) are the most common cancer in children and young men. TGCTs result from anomalies in the development of primordial germ cells (PGC), the embryonic precursors of gametes. Few factors involved in neoplastic transformation of PGCs have been identified in humans because the genetic component of TGCTs is complex and tumors initiate during embryogenesis. In 129/Sv mice, the only inbred strain of mice with an appreciable frequency of spontaneous TGCTs, tumors initiate around embryonic day 13.5 (E13.5). During this same developmental period, local retinoic acid (RA) levels in the developing gonad influences germ cell commitment to meiosis or mitotic arrest (the mitotic:meiotic switch). In female embryonic gonads, RA induces expression of Stra8, which functions in differentiation events required for germ cell entry into meiosis. In male embryonic gonads, RA is degraded, Stra8 expression is not induced, and gonocytes, the precursors of adult male germ cells, remain quiescent until after birth. The role of aberrant RA signaling and Stra8 expression in the premature differentiation of male embryonic gonocytes and the establishment of a tumor stem cell population in TGCT susceptible mice will be investigated. A combination of in vitro and in vivo teratoma formation assays, expression assays, loss-of-function mutations, and pluripotency and tumorigenicity assays will be used to characterize three Specific Aims. Aim 1 - Does aberrant retinoic acid signaling contribute to TGCT susceptibility and how are embryonic gonocytes exposed to RA? Aim 2 - Does Stra8 function in embryonic gonocyte differentiation and TGCT susceptibility? Aim 3 - Does a sub-population of embryonic gonocytes function as TGCT stem cells? These tests will reveal unique aspects of germ cell biology and TGCT tumorigenesis and may provide new targets for diagnosis and treatment of human TGCTs. PUBLIC HEALTH RELEVANCE: Defects in male germ cell development can result in testicular germ cell tumors (TGCTs). TGCTs are the most common cancer in children and young men. Despite considerable work in humans, little is known about the cellular process involved in early TGCT development. The mouse model of TGCTs will help guide potential future studies in humans and provide better diagnostic markers and targets for the identification and treatment of TGCTs.