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Yi-Xun LIU, Academician of CAS

Molecular mechanism of SSCs development/differentiation and Oocyte abnormal meiosis

Co-workers: Yan Zhang, Shou-Long Deng, Su-Ren Chen, Xiu-Xia Wang,Ji-Xin Tang,Cheng Jin, Jian Li, Jin-Mei Cheng,Xiao-Yu Li Xiao-Xia Hao Zhi-Peng Wang,Tie-cheng Sun Yu-qian Wang Aalia Batool

• LIU Group website


  Spermatogenesis takes place in cryptochild, scrotal hypothermia is essential for spermatogenesis.Cryptorchidism is infertile, but after operation could be recovered. We established both in vivo and in vitro 43℃ “heat stress” monkey/mouse models, and studied molecular mechanism of heat-induced temporal Sertoli cell (SC) de-differentiation and germ cell apoptosis.“heat stress” triggers a reversible changes in blood-testis-barrier (BTB) and associate protein disruption through SC via upstream factors such   as Wt-1, AR, Par6-Par3-aPKC-Cdc42 polarity complex and the related signal pathways, However, the temporal damage in the testicular cells and spermatogenesis would be completely recovered in a time-dependent manner after the“heat stress”. Our data strongly suggest that upstream factor CATA4/AR and its downstream effecter may play an important role in maintenance and re-establishment of BTB after the heat treatment. Using Gata4flox/flox, AMH-Cre (cKO GATA) and AR cKO (SCARKO) mice models, we observed the mutant testes exhibited an extensive loss of germ cells, followed by a Sertoli-cell-only syndrome; SCARKO causes EGF-EGFR signaling hyperactivation, and a failure in meiotic progression. EGFR pathway could be repressed by addition of the inhibitor AG1478 in the cultured neonatal Ar-knockout testicular cells, a normal meiosis process and haploid cells were observed. .Using the cKO aninal and the in vitro cell culture models 1) to dig into the mechanisms of niche cells self-renewal and differentiation of SSCs and their relationship with; 2). to investigate roles of Ezh2 in spermatogenesis; 3). To set up an in vitro human SSCs/testicular somatc cells coculture models for producing human functional sperms. The molecular gonad group has being also established projects to investigate molecular mechanisms underlying age-associated aneuploidy in mammalian oocytes,  and to identify the critical role of CUEDC2 in the oocytes meiotic maturation, that might provide a novel mechanism important for egg aneuploidy. Therefore we will set up a project to explore Cyclin B1 functions in faithful chromosome separation in meiosis with germ cell specific cyclin B1 cKO mouse model.

Generation of haploid sperm from AG1478-cultured SCARKO testis tissues in vitro.

Ccnb1 cKO mice A: Ccnb1fl/flMvh-Cre cKOmice construction; B: No difference moforlogicaly between the cKO and the control mice (8-week old)。C:No difference of the ovaries between the cKO and the control mice; D: No difference with H&E stain of the ovaries,the numbers of follicles nearly the same

Functional Sperms can be generated in our established “in vitro testis cell culture”About 4% and 60% of cells in the coculture were haploid round/elongating spermatids by 19- and 36-day, which could produce healthy competent offspring following microinsemination.



Plain english:
  1. Spermatogonial stem cells (SSCs) proliferation/differentiation and meiosis in the vitro testis cell culture system to produce functional haploid germ cells.
  2. To establish in vitro SSCs/testis somatic cell coculture models with Gata4-cKO and Ar-cKO mice to investigate the parine/autocrine regulation of spermatogenesis and the related signaling pathways.
  3. To study molecular mechanisms underlying age-associated aneuploidy in mammalian oocytes to explore Cyclin B1 functions in faithful chromosome separation in meiosis with germ cell specific cyclin B1 cKO mouse model.


Selected publications:

  1. Cheng JM1,2,3, Li J1,2, Tang JX1,2, Hao XX1,2, Wang ZP1,2, Sun TC1,2, Wang XX1, Zhang Y1, Chen SR1, Liu YX1. Merotelic Kinetochore Attachment in Oocyte Meiosis II Causes Sister Chromatids Segregation Errors in Aged Mice. 2017.16(15): 1404-1413
  2. Tang JX1,2, Li J1,2, Cheng JM1,2, Hu B3,4, Sun TC1,2, Li XY1,2, Batool A1,2, Wang ZP1,2, Wang XX1, Deng SL1, Zhang Y1, Chen SR1, Huang X3,4, Liu YX1,2. Requirement for CCNB1 in Mouse Spermatogenesis. 2017.8(10): E3142
  3. Jin C1,2, Zhang Y3,4, Wang ZP1,2, Wang XX1, Sun TC1,2, Li XY1,2, Tang JX1,2, Cheng JM1,2, Li J1,2, Chen SR1, Deng SL1, Liu YX3. EZH2 deletion promotes spermatogonial differentiation and apoptosis. 2017.154(5): 615-625
  4. Deng SL1, Sun TC2, Yu K3, Wang ZP1, Zhang BL4, Zhang Y1, Wang XX1, Lian ZX5, Liu YX6. Melatonin reduces oxidative damage and upregulates heat shock protein 90 expression in cryopreserved human semen. 2017.113: 347-354
  5. Chen SR, Chen M, Deng SL, Hao XX, Wang XX, Liu YX. Sodium-hydrogen exchanger NHA1 and NHA2 control sperm motility and male fertility.  Cell Death Dis.2016.7:E2152
  6. Deng SL, Chen SR, Wang ZP, Zhang Y, Tang JX, Li J, Wang XX, Cheng JM, Jin C, Li XY, Zhang BL, Yu K, Lian ZX, Liu GS, Liu YX. Melatonin promotes development of haploid germ cells from early developing spermatogenic cells of Suffolk sheep under in vitro condition. J Pineal Res. 2016. 60(4):435-47
  7. Chen SR, Hao XX, Zhang Y, Deng SL, Wang ZP, Wang YQ, Wang XX, Liu YX. Androgen receptor in Sertoli cells regulates DNA  double-strand break repair and chromosomal synapsis of spermatocytes partially through intercellular EGF-EGFR signaling.  Oncotarget. 2016. 7(14):18722-35
  8. Wen Q, Cheng CY, Liu YX. Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol. 2016. 59:89-98
  9. Chen, S. R. and Liu, Y. X. Myh11-Cre is Not Limited to Peritubular Myoid Cells and Interaction Between Sertoli and Peritubular Myoid Cells Needs Investigation. Proc Natl Acad Sci U S A .2016.113(17): E2352