Primordial germ cell differentiation and the initiation of testicular cancer

项目摘要 睾丸生殖细胞肿瘤(TGCT)是儿童和年轻人最常见的癌症。TGCT结果 原始生殖细胞(PGC)发育异常，原始生殖细胞是配子的胚胎前体。一些 在人类中已经确定了与PGCs肿瘤转化有关的因素，因为基因 TGCTs成分复杂，肿瘤发生于胚胎发育过程中。在129/Sv小鼠中，唯一的近亲繁殖 自发TGCT频率较高的小鼠品系，肿瘤在胚胎日前后开始 13.5(E13.5)。在同一发育时期，发育中的性腺中的局部维甲酸(RA)水平 影响生殖细胞对减数分裂或有丝分裂停止的承诺(有丝分裂：减数分裂开关)。在女性胚胎中 性腺，RA诱导Stra8的表达，Stra8在生殖细胞进入所需的分化事件中发挥作用 进入减数分裂。在男性胚胎性腺中，RA被降解，Stra8不被诱导表达，性腺细胞， 成年男性生殖细胞的前体细胞在出生后一直保持静止。RA异常信号转导途径的作用及机制 Stra8在男性胚胎性腺细胞早分化过程中的表达及体外培养 将对TGCT敏感小鼠的肿瘤干细胞数量进行调查。体外培养和体内培养的组合 体内畸胎瘤形成分析，表达分析，功能丧失突变，多能性和 致瘤性分析将被用来表征三个特定的目标。目的1.反常的维甲酸 信号对TGCT易感性有贡献，胚胎性腺细胞如何暴露于RA？目标2.做 Stra8在胚胎性腺细胞分化和TGCT易感性中的作用？目标3.是否有一个亚群 胚胎性腺细胞作为TGCT干细胞的功能？这些测试将揭示生殖细胞的独特方面 生物学和TGCT的肿瘤发生，并可能为人类TGCT的诊断和治疗提供新的靶点。

Project Summary 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 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.