Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line.
Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line.
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DOI：
10.1016/j.ydbio.2013.02.014
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发表时间：
2013-05-01
影响因子：
2.7
通讯作者：
Zarkower, David
中科院分区：
文献类型：
--
作者：
Krentz, Anthony D.;Murphy, Mark W.;Zhang, Teng;Sarver, Aaron L.;Jain, Sanjay;Griswold, Michael D.;Bardwell, Vivian J.;Zarkower, David
DMRT1(Doublesex and Mab-3 Related转录因子1)是脊椎动物睾丸发育的调节因子，与小鼠和人类的睾丸生殖细胞肿瘤有关。在胎鼠睾丸中，DMRT1以一种应变依赖的方式调节生殖细胞的多能性。在129Sv品系的小鼠中，DMRT1的缺失会导致90%的睾丸畸胎瘤，即由多个生殖层细胞组成的肿瘤；相比之下，这些肿瘤从未在C57BL/6J(B6)的DMRT1突变或混合遗传背景中被观察到。为了进一步研究DMRT1与遗传背景的相互作用，我们比较了129Sv和B6小鼠在胚胎15.5天(E15.5)，即明显的肿瘤形成之前，野生型和DMRT1突变胎儿睾丸中的mRNA表达。DMRT1的缺失导致两个菌株中重叠但不同的mRNAs的错误表达。受到选择性影响的mRNAs包括一些只在一个菌株或另一个菌株中改变表达的基因，还有一些在两个菌株中都改变了，但在其中一个菌株中改变的程度比另一个更大。特别是，在129Sv睾丸中DMRT1的缺失导致了比在B6睾丸中更严重的多能调节因子沉默失败。在人类睾丸生殖细胞肿瘤(TGCT)中，129Sv突变睾丸中的一些基因也存在调控错误，这表明小鼠和人类生殖细胞肿瘤的病因相似。表达谱显示，DMRT1也调节胎儿卵巢中的多能性基因，尽管DMRT1突变的女性不会患上畸胎瘤。通路分析表明，在DMRT1突变的胎儿睾丸中，包括Nodal、Notch和GDNF在内的几个信号通路被破坏。我们使用Nanos3-cre敲入等位基因进行条件性基因打靶，测试GDNF辅助受体Gfra1和Ret对畸胎瘤易感性的影响。在杂交到129Sv的动物的胎儿生殖细胞中，有条件地删除GFRA1而不是Ret导致了肿瘤发病率的温和但显著的增加。尽管这些杂交的遗传背景有一些差异，但这一结果与先前将畸胎瘤易感基因定位到包含GFRA1的区域的遗传图谱是一致的。利用Nanos3-cre，我们还发现DMRT1和Nanos3之间存在很强的遗传相互作用，这表明这两个基因在胎儿生殖细胞中具有平行的功能。最后，我们使用染色质免疫沉淀(CHIP-SEQ)分析来确定一些潜在的直接DMRT1靶标。这一分析表明，DMRT1通过转录抑制Esrrb、Nr5a2/Lrh1和Sox2来控制多能性。鉴于DMRT1参与人类TGCT的有力证据，本研究中确定的下游基因和途径为在人类疾病中发挥作用提供了潜在的有用候选基因。
Dmrt1(doublesex and mab-3 related transcription factor 1) is a regulator of testis development in vertebrates that has been implicated in testicular germ cell tumors of mouse and human. In the fetal mouse testis Dmrt1 regulates germ cell pluripotency in a strain-dependent manner. Loss of Dmrt1 in 129Sv strain mice results in a >90% incidence of testicular teratomas, tumors consisting cells of multiple germ layers; by contrast, these tumors have never been observed in Dmrt1 mutants of C57BL/6J (B6) or mixed genetic backgrounds. To further investigate the interaction between Dmrt1 and genetic background we compared mRNA expression in wild type and Dmrt1 mutant fetal testes of 129Sv and B6 mice at embryonic day 15.5 (E15.5), prior to overt tumorigenesis. Loss of Dmrt1 caused misexpression of overlapping but distinct sets of mRNAs in the two strains. The mRNAs that were selectively affected included some that changed expression only in one strain or the other and some that changed in both strains but to a greater degree in one versus the other. In particular, loss of Dmrt1 in 129Sv testes caused a more severe failure to silence regulators of pluripotency than in B6 testes. A number of genes misregulated in 129Sv mutant testes also are misregulated in human testicular germ cell tumors (TGCTs), suggesting similar etiology between germ cell tumors in mouse and man. Expression profiling showed that DMRT1 also regulates pluripotency genes in the fetal ovary, although Dmrt1 mutant females do not develop teratomas. Pathway analysis indicated disruption of several signaling pathways in Dmrt1 mutant fetal testes, including Nodal, Notch, and GDNF. We used a Nanos3-cre knock-in allele to perform conditional gene targeting, testing the GDNF coreceptors Gfra1 and Ret for effects on teratoma susceptibility. Conditional deletion of Gfra1 but not Ret in fetal germ cells of animals outcrossed to 129Sv caused a modest but significant elevation in tumor incidence. Despite some variability in genetic background in these crosses, this result is consistent with previous genetic mapping of teratoma susceptibility loci to the region containing Gfra1. Using Nanos3-cre we also uncovered a strong genetic interaction between Dmrt1 and Nanos3, suggesting parallel functions for these two genes in fetal germ cells. Finally, we used chromatin immunoprecipitation (ChIP-seq) analysis to identify a number of potentially direct DMRT1 targets. This analysis suggested that DMRT1 controls pluripotency via transcriptional repression of Esrrb, Nr5a2/Lrh1, and Sox2. Given the strong evidence for involvement of DMRT1 in human TGCT, the downstream genes and pathways identified in this study provide potentially useful candidates for roles in the human disease.
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