A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm
雄性生育能力的敲入小鼠模型:精子中哺乳动物特异性蛋白磷酸酶亚型 PP1y2 的基础
基本信息
- 批准号:10675027
- 负责人:
- 金额:$ 7.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlternative SplicingAmino Acid SequenceAnimalsBindingBiochemicalBrainCRISPR/Cas technologyCalcineurinCalciumCellsCharacteristicsClinicalComplexConsensusCouplesCyclic AMPCyclic AMP-Dependent Protein KinasesDevelopmentEnergy MetabolismEngineeringEnzymesEpididymisExonsFemaleFertilityGene ExpressionGenesGeneticGenomeGerm CellsGlycogen Synthase Kinase 3ImpairmentIn VitroInfertilityIntronsInvertebratesKnock-in MouseKnock-outKnockout MiceMale InfertilityMammalsMessenger RNAMetabolismMorphogenesisMusNucleotidesPenetrationPhenotypePhosphoproteinsPhysiological ProcessesProcessProtein IsoformsProtein phosphataseProteinsRNA SplicingRoleSecond Messenger SystemsSeminiferous tubule structureSignal TransductionSignaling ProteinSiteSomatic CellSperm MotilitySpermatogenesisSpermatogenic CellTestisTissuesTranscriptVertebratesWild Type Mousecell motilityegggenetic manipulationinorganic phosphateinsightknockout genemalemale fertilitymanmouse modelparalogous geneplacental mammalpromoterreproductive tractsperm cellsperm functionsperm proteintransgene expressionzygote
项目摘要
Spermatogenesis and the development of fertility competent sperm involve complex
processes in the testis, epididymis and female reproductive tract. These physiological processes
of sperm formation and development are difficult if not impossible to be recapitulated and studied
in vitro. Mouse models amenable to genetic manipulation are essential for understanding the basis
for male gamete function.
Considerable progress has been made in identifying signaling proteins essential for
sperm function which include components of cyclic AMP metabolism, proteins controlling sperm
intracellular pH and calcium levels of sperm in the epididymis and in the female reproductive tract.
Numerous gene knock out approaches targeting the signaling proteins involved in metabolism and
in the action of second messengers result in male infertility. Yet the mechanistic basis for normal
and disrupted sperm function remains largely unknown.
We discovered that a protein phosphatase PP12, which is one of two paralogs from
one gene Ppp1cc, is highly expressed in testis and present in sperm. The other paralog, PP11, is
expressed in brain and several somatic cells and tissues and cells. Two other genes encode the
PP1 and PP1 isoforms. These four PP1 isoforms are highly conserved between themselves and
across species. The isoform PP12 is present only in placental mammals suggesting an essential
role for it in the unique features of mammalian sperm function. It is notable that sperm from other
species contain one of the protein phosphate isoforms PP11, PP1 or PP1. The targeted knock
out of Ppp1cc results in male infertility. Transgenic expression of PP12, but not PP11, driven by
a testis specific promoter restores fertility in the Ppp1cc null mice, highlighting the essential
requirement for PP12. In this proposal we will examine a mouse line we have generated where
the Ppp1cc gene is edited by Crispr/Cas9 to express PP11 alone in testis. Determination of the
impaired functions in PP11 bearing mice and sperm should lead to the identification of key proteins
essential for normal sperm function.
Male infertility is responsible for about 10% of infertile couples. Identification of the
causes and treatments for male infertility are limited. A number of factors can affect male infertility:
major factors are likely environmental or genetic. This mouse model bearing the non-mammalian
PP1 isoform in sperm should also be valuable in not only understanding the significance of the
presence of PP12 in all mammals but also in understanding the biochemical basis for fertility and
infertility in man.
精子发生与具有生育能力的精子发育关系复杂
睾丸、附睾部和女性生殖道的突起。这些生理过程
即使不是不可能,也很难概括和研究。
在试管中。能够进行基因操作的小鼠模型对于理解这一基础是必不可少的
用于雄配子功能。
在识别信号转导蛋白方面已经取得了相当大的进展
精子功能包括环磷酸腺苷代谢成分、控制精子的蛋白质
附睾和女性生殖道内精子的细胞内pH和钙水平。
大量针对信号蛋白的基因敲除方法涉及新陈代谢和
在第二信使的作用下会导致男性不育。然而,正常的机械论基础
而精子功能受损在很大程度上仍是未知的。
我们发现了一种蛋白磷酸酶Pp12,它是来自
Ppp1cc基因在睾丸中高度表达,在精子中存在。另一个Paralog,pp11,
在大脑和几个体细胞以及组织和细胞中表达。另外两个基因编码
Pp1和pp1亚型。这四种PP1亚型之间高度保守
跨物种。Pp12的亚型只存在于胎盘哺乳动物中,这表明
对于它在哺乳动物精子功能中的独特功能。值得注意的是,来自其他地方的精子
物种含有蛋白质磷酸异构体pp11、pp1或pp1中的一种。定向敲打
Ppp1cc的缺失会导致男性不育。PP12的转基因表达,而不是PP11的转基因表达
睾丸特异性启动子可恢复pp1cc基因缺失小鼠的生育能力,突出了
对于pp12的要求。在本提案中,我们将检查我们在以下位置生成的鼠标行
Pp1cc基因由Crispr/Cas9编辑,在睾丸中单独表达pp11。确定了
携带Pp11的小鼠和精子的功能受损应导致关键蛋白的鉴定
对于正常的精子功能来说是必不可少的。
男性不育约占不育夫妇总数的10%。身份识别
男性不育的原因和治疗是有限的。影响男性不育的因素有很多:
主要因素可能是环境或遗传因素。这是一种非哺乳动物的小鼠模型
精子中的PP1亚型也应该不仅在理解PP1的意义上有价值
Pp12在所有哺乳动物中的存在,也有助于理解生育和
男性不育症。
项目成果
期刊论文数量(0)
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SRINIVASAN VIJAYARAGHAVAN其他文献
SRINIVASAN VIJAYARAGHAVAN的其他文献
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{{ truncateString('SRINIVASAN VIJAYARAGHAVAN', 18)}}的其他基金
A knock-in mouse model for male fertility: basis for the mammal-specific protein phosphatase isoform PP1y2 in sperm
雄性生育能力的敲入小鼠模型:精子中哺乳动物特异性蛋白磷酸酶亚型 PP1y2 的基础
- 批准号:
10527437 - 财政年份:2022
- 资助金额:
$ 7.6万 - 项目类别:
Identification of Phospho-proteins Regulating Sperm Function
调节精子功能的磷酸蛋白的鉴定
- 批准号:
9333123 - 财政年份:2016
- 资助金额:
$ 7.6万 - 项目类别:
Protein Phosphatase Action in Mammalian Spermatogenesis and Sperm Function
蛋白磷酸酶在哺乳动物精子发生和精子功能中的作用
- 批准号:
8289861 - 财政年份:2012
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Sperm Function by Protein Phosphorylation
蛋白质磷酸化调节精子功能
- 批准号:
8051037 - 财政年份:2010
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Sperm Function by Protein Phosphorylation
蛋白质磷酸化调节精子功能
- 批准号:
7846469 - 财政年份:2009
- 资助金额:
$ 7.6万 - 项目类别:
The Role of 14-3-3 Proteins in Oogenesis and Early Development
14-3-3 蛋白在卵子发生和早期发育中的作用
- 批准号:
9170889 - 财政年份:2009
- 资助金额:
$ 7.6万 - 项目类别:
REGULATION OF SPERM FUNCTION BY PROTEIN PHOSPHORYLATION
蛋白质磷酸化对精子功能的调节
- 批准号:
6637061 - 财政年份:2001
- 资助金额:
$ 7.6万 - 项目类别:
REGULATION OF SPERM FUNCTION BY PROTEIN PHOSPHORYLATION
蛋白质磷酸化对精子功能的调节
- 批准号:
6521294 - 财政年份:2001
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Sperm Function by Protein Phosphorylation
蛋白质磷酸化调节精子功能
- 批准号:
7534804 - 财政年份:2001
- 资助金额:
$ 7.6万 - 项目类别:
Regulation of Sperm Function by Protein Phosphorylation
蛋白质磷酸化调节精子功能
- 批准号:
7659309 - 财政年份:2001
- 资助金额:
$ 7.6万 - 项目类别:
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