Behr Rüdiger, Sackett Sara D, Bochkis Irina M, Le Phillip Phuc, Kaestner Klaus H
Department of Genetics, University of Pennsylvania Medical School, 415 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
Dev Biol. 2007 Jun 15;306(2):636-45. doi: 10.1016/j.ydbio.2007.03.525. Epub 2007 Apr 5.
Foxa1, 2 and 3 (formerly HNF-3alpha, -beta and -gamma) constitute a sub-family of winged helix transcription factors with multiple roles in mammalian organ development. While all three Foxa mRNAs are present in endoderm derivatives including liver and pancreas, only Foxa3 is expressed in the testis. Here we demonstrate by genetic lineage tracing that Foxa3 is expressed in postmeiotic germ and interstitial Leydig cells. The germinal epithelium of Foxa3-deficient testes is characterized by a loss of germ cells secondary to an increase in germ cell apoptosis that ultimately leads to a Sertoli cell-only syndrome. Remarkably, not only the Foxa3(-/-) mice but also Foxa3(+/-) mice exhibited loss of germ cells. This cellular phenotype caused significantly reduced fertility and testis weight of both Foxa3(-/-) and Foxa3(+/-) mice. Using microarray analysis, we found a dramatic downregulation of the zinc finger protein 93 and the testicular tumor-associated paraneoplastic Ma antigen (PNMA) and increased expression of a number of genes including zinc finger protein 94 and several kallikrein 1-related peptidases which could account for at least part of the observed phenotype. In summary, we have identified Foxa3 as a transcriptional regulator with a dominant phenotype in germ cell maintenance and suggest FOXA3 as a potential candidate gene for subfertility in man.
叉头框蛋白A1、A2和A3（以前称为肝细胞核因子3α、β和γ）构成了一个翼状螺旋转录因子亚家族，在哺乳动物器官发育中具有多种作用。虽然所有三种叉头框蛋白A的信使核糖核酸都存在于包括肝脏和胰腺在内的内胚层衍生物中，但只有叉头框蛋白A3在睾丸中表达。在这里，我们通过基因谱系追踪证明，叉头框蛋白A3在减数分裂后的生殖细胞和睾丸间质细胞中表达。叉头框蛋白A3缺陷型睾丸的生精上皮细胞的特征是，生殖细胞凋亡增加导致生殖细胞数量减少，最终导致唯支持细胞综合征。值得注意的是，不仅叉头框蛋白A3基因敲除小鼠，而且叉头框蛋白A3杂合子小鼠也出现了生殖细胞缺失的情况。这种细胞表型导致叉头框蛋白A3基因敲除小鼠和叉头框蛋白A3杂合子小鼠的生育能力和睾丸重量显著降低。通过微阵列分析，我们发现锌指蛋白93和睾丸肿瘤相关的副肿瘤马抗原（PNMA）显著下调，包括锌指蛋白94和几种激肽释放酶1相关肽酶在内的一些基因表达增加，这可能至少部分解释了观察到的表型。总之，我们已经确定叉头框蛋白A3是生殖细胞维持中具有显性表型的转录调节因子，并提出叉头框蛋白A3是人类生育力低下的潜在候选基因。
