睾丸特异性基因GGNBP1在精子发生中的作用及其机制研究

MMAF (multiple morphological abnormalities of the flagella), result from dysplastic sperm flagella, is one of the important causes of male infertility. Previous studies have reported that the mutation of some genes can lead to MMAF. However, the pathogenesis of most MMAF remains unclear. Our previous study found that knockout of testis-specific gene GGNBP1 in mouse germ cells can lead to considerable loss of germ cells and severe deformity of sperm tail, suggesting that this mutation may be one cause of spermatogenic disorder and MMAF. The present study is to further explore the role of GGNBP1 in spermatogenesis by observing fertility, the number and morphology of sperm in GGNBP1 knockout mouse; we also plan to detect the location and expression of GGNBP1 in various stages of spermatogenesis, and to explore it relationship with spermatogenic phase and major events; the construction and function of mitochondria was also detected in the sperm with GGNBP1 deletion. This study will help to understand the pathogenesis of abnormal spermatogenesis and provide a new target for the diagnosis and treatment of male infertility.

由于精子鞭毛发育异常导致的鞭毛多种形态异常（MMAF）是男性不育的重要原因之一，既往有研究报道某些基因突变可导致MMAF，然而大多MMAF的病因仍不明确。我们前期研究发现将睾丸特异性基因GGNBP1敲除可导致小鼠生殖细胞大量丢失及精子尾部严重畸形，推测其突变可能是精子发生异常和MMAF的致病原因之一。本项目拟进一步深入研究GGNBP1在精子发生中的作用，观察GGNBP1敲除小鼠生育能力、精子数目形态等表型变化；检测GGNBP1在精子发生过程中各阶段的定位及表达，并将其与精子发生的时相以及主要事件相联系；同时利用在体敲除GGNBP1的小鼠模型，观察GGNBP1基因缺失后精子线粒体的结构及功能变化。本研究将有助于深入了解精子发生异常的致病机制，为男性不育的诊治提供新的靶点。

精子鞭毛发育异常导致的鞭毛多种形态异常（MMAF）是男性不育的重要原因之一，然而大多MMAF的病因仍不明确。本项目通过构建睾丸特异性基因配子生成素结合蛋白1（GGNBP1）敲除小鼠，发现其发现其存在两种表型：一类表现为雄性不育，而另一类完全可育。通过表型分析发现GGNBP1敲除不育小鼠生精上皮出现空泡，附睾中出现大量畸形精子，并且精子活力显著降低，对GGNBP1敲除不育小鼠生精过程进行检测，发现GGNBP1敲除后影响精子头部塑形过程，导致畸形精子的产生；而GGNBP1敲除可育小鼠生精上皮组织形态正常，附睾中精子数目未见降低，精子活力与对照组类似，进一步在GGNBP1敲除可育小鼠中注射低剂量的双酚A，发现其可以诱导GGNBP1敲除小鼠产生畸形精子并导致精子活力降低。因此，GGNBP1在维持精子发生中正常形态生成及应对环境压力导致的生精损伤中都具有重要作用，GGNBP1突变可能是MMAF及男性不育的重要病因之一。

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