Reynolds Nicola, Collier Brian, Bingham Victoria, Gray Nicola K, Cooke Howard J
Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, UK.
RNA. 2007 Jul;13(7):974-81. doi: 10.1261/rna.465507. Epub 2007 May 25.
DAZ-related genes are essential for gametogenesis in diverse metazoa: in human males, a loss of DAZ genes is associated with infertility. These genes, expressed only in germ cells, regulate the translation of a yet undefined set of specific transcripts, and loss of function results in numerous defects throughout the mitotic and meiotic process of germ cell development. In a mouse model, absence of the autosomal Dazl gene results in a final block at zygotene of meiotic prophase. Sycp3 is also essential for meiosis, specifically for the formation of the synaptonemal complex lateral element with a mouse knockout model displaying a block in meiotic prophase similar to the Dazl knock out. Sycp3 was identified as a potential target for translational regulation by Dazl in male mouse germ cells. This was confirmed by both RNA binding and translation assays. In the Dazl knockout mouse model, Sycp3 protein levels were decreased, indicating that Dazl is required for efficient translation of the Sycp3 mRNA in vivo. Taken together these data support Sycp3 as a biologically relevant target of Dazl-mediated translation in mammals. This suggests that azoospermia associated with a decrease in DAZ gene function in humans may in part be a consequence of failure at synapsis caused by reduced levels of SYCP3 protein.
与DAZ相关的基因对于多种后生动物的配子发生至关重要:在人类男性中,DAZ基因的缺失与不育有关。这些基因仅在生殖细胞中表达,调控一组尚未明确的特定转录本的翻译,功能丧失会导致生殖细胞发育的有丝分裂和减数分裂过程中出现众多缺陷。在一个小鼠模型中,常染色体Dazl基因的缺失导致减数分裂前期偶线期的最终阻滞。Sycp3对减数分裂也至关重要,特别是对于联会复合体侧生元件的形成,一个小鼠基因敲除模型显示减数分裂前期出现阻滞,类似于Dazl基因敲除。Sycp3被确定为雄性小鼠生殖细胞中Dazl翻译调控的潜在靶点。这通过RNA结合和翻译实验得到了证实。在Dazl基因敲除小鼠模型中,Sycp3蛋白水平降低,表明Dazl是体内Sycp3 mRNA高效翻译所必需的。综合这些数据支持Sycp3作为哺乳动物中Dazl介导翻译的生物学相关靶点。这表明人类中与DAZ基因功能降低相关的无精子症可能部分是由于SYCP3蛋白水平降低导致联会失败的结果。