GENE EXPRESSION IN SPERMATOGENIC CELLS

生精细胞中的基因表达

• 批准号: 2574443
• 负责人: E M EDDY
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2574443
• 关键词: adenosine triphosphate; cytoskeleton; developmental genetics; endopeptidases; enzyme activity; enzyme induction /repression; flagellin; gene mutation; genetic promoter element; genetically modified animals; glyceraldehyde 3 phosphate dehydrogenase; laboratory mouse; male; protamines; site directed mutagenesis; spermatogenesis

The long-term goal of these studies is to determine the mechanisms that regulate development of germ cells in the male. This is being approached by identifying genes that are expressed specifically in male germ cells and are up-regulated during particular phases of male germ cell development. These are referred to as chauvinist genes because male germ cells favor their expression with strong prejudice. They include germ cell homologue genes, unique genes, and genes expressing unique transcripts. Germ cell homologue genes are expressed only in spermatogenic cells, but are closely related to other genes expressed in somatic cells. One of these is glyceraldehyde 3-phosphate dehydrogenase (Gapd-s), likely to be important in male fertility and reproductive toxicology. The GAPD-S enzyme is "off" in spermatids and "on" in sperm and has a key role in regulating the generation of ATP required for fertilization. The expression of the Gapd-s mRNA and GAPD-S protein have been determined, the minimum promoter region required for transcription in transgenic mice has been identified, and the phenotype produced by a knockout of the Gapd-s gene is being determined. Studies are also underway to produce targeted mutations in three unique genes that are expressed only in spermatogenic cells and lack somatic cell isoforms. These genes encode proteins believed to have critical roles in sperm-egg binding (fertilin beta), spermatid nuclear condensation (protamine 1), and flagellar structural integrity (Fscl). The fertilin beta protein is a sperm surface component that has metalloprotease and disintegrin domains, and binds specifically to alpha1beta6 integrin on the egg surface. Protamine 1 is a highly basic protein that replaces histones during the compaction of DNA in the forming sperm head. Fscl is a major cytoskeletal component of the sperm flagellum. Mutations in the genes are expected to produce disruption of sperm formation or fertilization in homozygous male mice. The predicted phenotypes are similar to conditions observed in some infertile men and the results will be valuable both for understanding the development and function of sperm and for determining the possible roles of mutations in these genes in human infertility.

这些研究的长期目标是确定 调节男性生殖细胞的发育。 这是正在进行的 通过识别在男性生殖细胞中特异性表达的基因 并且在雄性生殖细胞的特定阶段被上调 发展 这些被称为沙文主义基因，因为男性生殖 细胞以强烈的偏见支持它们的表达。 包括胚芽 细胞同源基因、独特基因和表达独特基因 成绩单 生殖细胞同源基因仅在 生精细胞，但与其他基因表达密切相关， 体细胞 其中之一是甘油醛3-磷酸脱氢酶 （Gapd-s），可能在男性生育力和生殖 毒理学 GAPD-S酶在精子细胞中是“关闭”的，而在精子中是“打开”的。 并在调节所需ATP的产生方面起着关键作用， 受精 Gapd-s mRNA和Gapd-S蛋白的表达与Gapd-s的表达呈负相关。 已经确定，转录所需的最小启动子区域 在转基因小鼠中已经被鉴定，并且由转基因小鼠产生的表型 Gapd-s基因的敲除正在确定中。研究也 正在进行中的三个独特基因的靶向突变， 仅在生精细胞中表达，缺乏体细胞同种型。 这些基因编码的蛋白质被认为在精卵发育中起着关键作用。 结合（受精素β），精子细胞核凝聚（鱼精蛋白1）， 和鞭毛结构完整性（Fscl）。 受精素β蛋白是 一种精子表面成分，含有金属蛋白酶和去整合素 结构域，并特异性结合于卵细胞上的α 1 β 6整合素 面 鱼精蛋白1是一种高度碱性的蛋白质， 在精子头部形成的DNA压缩过程中。 Fscl是一个专业 精子鞭毛的细胞骨架成分。 的基因中的突变 预期会破坏精子形成或受精 在纯合子雄性小鼠中。 预测的表型与 在一些不育男性中观察到的情况，结果将是 对了解精子的发育和功能， 用于确定这些基因突变在人类中的可能作用， 不孕