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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. Chen SR, Liu YX. 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 Apr 1. pii: 201602873.
  2.  Chen SR, 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.
  3. 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. doi: 10.1111/jpi.12327.
  4. 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. doi: 10.18632/oncotarget.7916.
  5. Wen Q, Cheng CY, Liu YX. Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol. 2016. pii: S1084-9521(16)30067-2. doi: 10.1016/j.semcdb.2016.03.003.
  6. Gao F, Zhang J, Wang X, Yang J, Chen D, Huff V, Liu YX. Wt1 functions in ovarian follicle development by regulating granulosa cell differentiation. Hum Mol Genet. 2014; 23(2):333-41.
  7. Zhang CP, Yang JL, Zhang J, Li L, Huang L, Ji SY, Hu ZY, Gao F, Liu YX: Notch signaling is involved in ovarian follicle development by regulating granulosa cell proliferation. Endocrinology 2011;152(6):2437-47. Epub 2011 Mar 22.
  8. Yang JL,Zhang CP,Li L,Huang L,Ji SY,Lu CL,Fan CH,Cai H,Ren Y,Hu ZY,Gao F and Liu YX (2010:Testosterone induces redistribution of forkhead box-3a and down-regulation of growth and differentiation factor 9 messenger ribonucleic acid expression at early stage of mouse folliculogenesis. Endocrinology 2010 Feb;151(2):774-82.
  9. Min Chen, Jun-Ling Yang, Cui-Ling Lu, Tao Liu, Wei Yang, Jian Guo, Shi-Xin Tao, Xiao-Qian Hu, Cui-Hong Fan, Zhao-Yuan Hu, Fei Gao and Yi-Xun Liu (2008): Effect of heat stress on expression of junction-associated molecules and upstream factor AR and WT1 in monkey and rat Sertoli cells Endocrinology, 2008 Oct;149(10):4871-82.
  10. Guo J, Tao SX, Chen M, Shi YQ, Zhang ZQ, Li YC, Zhang XS, Hu ZY, Liu YX (2006):.Heat treatment induces liver receptor homolog-1 expression in monkey and rat Sertoli cells. Endocrinology. 2007 Mar;148(3):1255-65.
  11. Zhang XS, Zhang ZH, Jin X, Wei P, Hu XQ Chen M, Lu CL1, Lue YH 2, Guo SH1, Yuan JX 1, Hu ZY1, Han CS 1, Hikim APS 2, Swerdloff RS.2, Wang C and Liu YX. Dedifferentiation of Adult monkey Sertoli cells Through Activation of ERK1/2 Kinase Induced by Heat treatment Endocrinology .2006, 147(3):1237-1245