PDF(Pubmed)
Abstract：
Azoospermia is a high risk factor for testicular germ cell tumors, whose underlying molecular mechanisms remain unknown. In a genome-wide association study to identify novel loci associated with human non-obstructive azoospermia (NOA), we uncovered a single nucleotide polymorphism (rs1887102, P=2.60 ×10-7) in a human gene FOXN3. FOXN3 is an evolutionarily conserved gene. We used Drosophila melanogaster as a model system to test whether CHES-1-like, the Drosophila FOXN3 ortholog, is required for male fertility. CHES-1-like knockout flies are viable and fertile, and show no defects in spermatogenesis. However, ectopic expression of CHES-1-like in germ cells significantly reduced male fertility. With CHES-1-like overexpression, spermatogonia fail to differentiate after four rounds of mitotic division, but continue to divide to form tumor like structures. In these testes, expression levels of differentiation factor, Bam, were reduced, but the expression region of Bam was expanded. Further reduced Bam expression in CHES-1-like expressing testes exhibited enhanced tumor-like structure formation. The expression of daughters against dpp (dad), a downstream gene of dpp signaling, was upregulated by CHES-1-like expression in testes. We found that CHES-1-like could directly bind to the dpp promoter. We propose a model that CHES-1-like overexpression in germ cells activates dpp expression, inhibits spermatocyte differentiation, and finally leads to germ cell tumors.
摘要：
无精子症是睾丸生殖细胞肿瘤的高危因素,其潜在的分子机制仍然未知。在鉴定与人类非梗阻性无精子症（NOA）相关的新基因座的全基因组关联研究中，我们发现了人基因FOXN3中的单核苷酸多态性（rs1887102，P=2.60×10-7）。FOXN3是一个进化上保守的基因。我们使用果蝇作为模型系统来测试CHES-1是否类似，果蝇FOXN3直系同源，是男性生育所必需的。类似CHES-1的敲除果蝇是可行和肥沃的，精子发生没有缺陷。然而,生殖细胞中CHES-1样的异位表达显着降低了男性的生育力。CHES-1样过度表达,精原细胞在四轮有丝分裂后无法分化，但继续分裂形成肿瘤样结构。在这些睾丸中，分化因子的表达水平，砰,减少了，但是Bam的表达区域扩大了。表达CHES-1样的睾丸中Bam表达的进一步降低表现出增强的肿瘤样结构形成。女儿反对民进党(爸爸)的表达，dpp信号的下游基因，睾丸中CHES-1样表达上调。我们发现CHES-1-like可以直接结合dpp启动子。我们提出了一个模型，CHES-1-样过表达在生殖细胞激活dpp表达，抑制精母细胞分化，最后导致生殖细胞肿瘤.
