Testicular germ cell tumors arise in the absence of sex-specific differentiation.
Testicular germ cell tumors arise in the absence of sex-specific differentiation.
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DOI：
10.1242/dev.197111
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发表时间：
2021-05
期刊：
影响因子：
4.6
通讯作者：
N. Webster;Rebecca L. Maywald;Susan M. Benton;Emily P. Dawson;Oscar D. Murillo;Emily L. LaPlante;A. Milosavljevic;Denise G. Lanza;Jason D. Heaney
中科院分区：
文献类型：
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作者：
N. Webster;Rebecca L. Maywald;Susan M. Benton;Emily P. Dawson;Oscar D. Murillo;Emily L. LaPlante;A. Milosavljevic;Denise G. Lanza;Jason D. Heaney
为了响应来自胚胎睾丸的信号，生殖细胞内在因子 NANOS2 协调多能样原始生殖细胞向单能精原干细胞分化所必需的转录程序。新的证据表明，遗传风险因素通过破坏性别特异性分化而导致睾丸生殖细胞肿瘤的发生。在这里，使用睾丸畸胎瘤的 129.MOLF-Chr19 小鼠模型和 NANOS2 报告等位基因，我们报告肿瘤发生所需的发育表型，包括未能进入有丝分裂停滞、保留多能性和延迟的性别特异性分化，是无法表达 NANOS2 的生殖细胞亚群所独有的。单细胞 RNA 测序显示，胚胎第 15.5 天 NANOS2 缺陷的生殖细胞和胚胎癌细胞形成了富含 MYC 信号、NODAL 信号和引发多能性的转录谱。此外，谱系追踪实验表明，胚胎癌细胞完全源自无法表达 NANOS2 的生殖细胞。我们的结果表明，NANOS2 是多种遗传风险因素影响肿瘤易感性的纽带。我们认为，在缺乏性别规范的情况下，发育中的睾丸固有的信号驱动生殖细胞转化。
In response to signals from the embryonic testis, the germ cell intrinsic factor NANOS2 coordinates a transcriptional program necessary for the differentiation of pluripotent-like primordial germ cells toward a unipotent spermatogonial stem cell fate. Emerging evidence indicates that genetic risk factors contribute to testicular germ cell tumor initiation by disrupting sex-specific differentiation. Here, using the 129.MOLF-Chr19 mouse model of testicular teratomas and a NANOS2 reporter allele, we report that the developmental phenotypes required for tumorigenesis, including failure to enter mitotic arrest, retention of pluripotency and delayed sex-specific differentiation, were exclusive to a subpopulation of germ cells failing to express NANOS2. Single-cell RNA sequencing revealed that embryonic day 15.5 NANOS2-deficient germ cells and embryonal carcinoma cells developed a transcriptional profile enriched for MYC signaling, NODAL signaling and primed pluripotency. Moreover, lineage-tracing experiments demonstrated that embryonal carcinoma cells arose exclusively from germ cells failing to express NANOS2. Our results indicate that NANOS2 is the nexus through which several genetic risk factors influence tumor susceptibility. We propose that, in the absence of sex specification, signals native to the developing testis drive germ cell transformation.