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A key finding unveiled the mystry of flaggela development in human sperm, leading by researchers from west china second university Hospital, Sichuan University

2019-03-01 16:41:55

In sexual reproduction, male germ cells,under the chemotaxis in female genital tract, voluntarily swim until bindingwith the egg cells, then the oosperms are formed, which is a sign for theorigin of life. The flagella of human sperm is the primary structure what leadsto spontaneous motions of a sperm. However, what is the initial stage in theflagella formation? The major proteins in the formation of this structure areclosely related to the development of human sperm flagellum,  yet the molecular mechanism still remainsunclear.

Recently, the paper entitledLoss-of-functionmutations in QRICH2 cause male infertility with multiple morphologicalabnormalities of the sperm flagellapublished inprestigious international journalNatureCommunicationsunravel the mystery. This work was the result ofcooperation leaded by professor Xu Wenming from Western Institute ofMaternal and Child Medicine and professor Yue Huanxun from Human sperm bank ofWCSUH, Sichuan University. The first author of this paper is the postdoctorShen Ying. Professor Xu Wenming and Professor Yue Huanxun are co-correspondingauthors of this paper.

The study was initiated from the discoveryin the andrology clinic of our hospital of infertile males in consanguineousmating families of Ethnic Minorities in Southwest China. Via whole exomesequencing, The authors identified a candidate gene QRICH2 crucial for flagelladevelopment in sperm tail. The whole exon sequencing revealed a nonsensemutation (c.192G>A.p.L64*) in exon 3 and a nonsense mutation(c.3037C>Tp.R1013*) in exon 4 of QRICH2 in the consanguineousmarriage-induced male infertility family, both mutations lead to the phenotypeof multiple morphological abnormalities of the flagella (MMAF). Subsequently,the Cas9 knockout mice model was established, and by quantitative proteomicsexperiments, remarkable down-regulated proteins related to the development andenergy me-x-tabolism of flagella in sperm tail were found in QRICH2 knockout mice.The study also showed that QRICH2 can regulate the ex-x-pression of ODF2, which isknown as a pivotal protein for stabilizing tubulin development inregulation of sperm motility. Further mechanism research found that QRICH2 is amaster switch for the ex-x-pression of flagellar key proteins in sperm tail,respectively regulating the ex-x-pression of AKAP3 and CABYR at the levels oftranscription and translation, and the quantitative proteomic results alsoindicated the key role of QRICH2 in sperm flagella development. Moreover, thedistribution of QRICH2 in sperm tail flagella was observed by high resolutionmicroscope, clarifying its location in flagella development. These studiesfurther demonstrated that QRICH2 plays a vital regulatory role in thedevelopment of sperm fibrous sheath.

It is worth mentioning that this study isthe result of close collaboration between basic research and clinical practice.Using the family samples provided by the human sperm bank, the research teamconducted linkage analysis, gene knockout and multi-function analysis,meanwhile, cooperated with professor Zhao Xudong of Kunming Institute of AnimalSciences, Chinese Academy of Sciences, director Zhang Feng of Human Sperm Bankin Fudan University and National Key Laboratory of Reproductive Medicine,Nanjing Medical University. By intensive study, they revealed a key gene forsperm motility. Moreover, the research team has discovered heterozygousmutations that may have pathological significance in 5% of asthenospermia (themost common cause of male infertility) samples, which provide a potential  key target for genetic diagnosis of maleinfertility.