Primordial germ cell differentiation and the initiation of testicular cancer

项目摘要 睾丸生殖细胞肿瘤（TGCT）是儿童和年轻男性中最常见的癌症。TGCT结果 原始生殖细胞（配子的胚胎前体）发育异常。几 已经在人类中鉴定了涉及PGC肿瘤转化的因子， TGCT的组成成分复杂，肿瘤在胚胎发生期间开始。在129/Sv小鼠中， 一种自发性TGCT发生频率较高的小鼠品系，肿瘤在胚胎期开始 13.5（E13.5）。在同一发育时期，发育性腺中的局部视黄酸（RA）水平 影响生殖细胞对减数分裂或有丝分裂停滞的承诺（有丝分裂：减数分裂转换）。女性胚胎 在性腺中，RA诱导Stra 8的表达，Stra 8在生殖细胞进入所需的分化事件中起作用 进入减数分裂在雄性胚胎性腺中，RA被降解，Stra 8表达未被诱导，而生殖细胞， 成年男性生殖细胞的前体，直到出生后才保持静止。异常RA信号传导的作用， Stra 8基因在男性胚胎生殖细胞早期分化中的表达及基因组学研究 将研究TGCT易感小鼠中的肿瘤干细胞群体。体外和体内的组合 体内畸胎瘤形成测定、表达测定、功能丧失突变和多能性， 致瘤性试验将用于表征三种特定目的。目标1.异常的视黄酸 信号传导有助于TGCT易感性，胚胎生殖细胞如何暴露于RA？目标二。并 Stra 8在胚胎生殖细胞分化和TGCT易感性中的作用目标3.是否有一个 胚胎生殖细胞作为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.