Zhang Lab

The major focus of my research is to study molecular mechanism of ciliogenesis/spermatogenesis, transcriptional regulation of ciliary genes, and novel functions of mammalian central apparatus proteins.

We discovered that mouse meiosis expressed gene 1 (MEIG1) is a master regulator of spermiogenesis, the final phase of spermatogenesis, when sperm flagella are formed. Mice lacking Meig1 are completely infertile, associated with failure of formation of sperm flagella. MEIG1 is localized in the manchette of the elongating spermaids, where it forms a complex with PACRG protein and the complex is essential to transport cargo proteins along the manchette microtubules for sperm flagella formation.

Intraflagella transport (IFT) is the most important mechanism for ciliogenesis. There are about twenty Ift genes, inactivation of these genes using traditional gene target strategy usually gives rise to death before sex maturity. We are using conditional gene target strategy to inactivate these genes only in male germ cells to investigate their roles in male fertility.

Sox-5 is a member of a family of genes that shows homology to the high motility group (HMG) box region of the testis determining gene, SRY. The mouse Sox5 gene encodes two major transcripts: the longer Sox5 isoform L-Sox5, and a shorter isoform, S-Sox5. The first exon of the S-Sox5 transcript is a non-translated exon; it is not present in the L-Sox5 transcript. The two SOX5 proteins have different tissue distributions. S-SOX5 was originally cloned from mouse testis, and indirect immunofluorescence demonstrated that S-SOX5 protein is localized in the nuclei of post-meiotic round spermatids. Our preliminary studies demonstrated that S-Sox5 is only expressed in tissues with motile cilia, including the brain, lungs, and particularly in the testis. We hypothesize that S-SOX5 regulates expression of a suite of genes that are essential for motile cilia/sperm flagella formation and function. We have generated a conditional mouse mutant model, and the role of S-SOX5 in vivo is being studied.

The central pair apparatus is a unique structure in the motile cilia. In Chlamydomonas, proteins localized in this structure play a single role: regulating/modulating cilia motility. However, we discovered that functions of their mammalian orthologues are significantly different. One example if sperm associated antigen 6 (Spag6) gene. We discovered that SPAG6 not only regulates cilia motility, but also regulates cytoskeleton/microtubule functions. The gene controls cell morphology, proliferation, migration, adhesion, division, vesicle transport and ciliogenesis of primary cilia and autophagy. The Spag6-deficient mice not only developed sperm motility defect, they also lost hearing and showed defects in immune synapse and spermatogensis, et al. Expression of SPAG6 is dramatically increased in human cancers. The mechanisms of SPAG6’s functions are being studied.

Zhibing Zhang Ph. D, M.D
Associate Professor
Physiology
Obsterics/Gynercology

Qian Huang – Ph.D Student

Qian Huang received her Bachelor of Science Degree from Wuhan University of Science and Technology in 2017. She was then accepted to begin a Master/PhD track at the same university. In 2017, she joined Dr. Zhang’s lab in Virginia Commonwealth University. She then moved to Mott Center with the lab in 2018. Her study focuses on the role of COP9 signalosome complex subunit 5 (Cops5) in spermatagenesis. She discovered that COPS5 is essential to maintain male germ cell survival and acrosome biogenesis in mice. She is currently studying the mechanism of how Cops5 regulates spermatogenesis.

Wei Li M.D. – Postdoctor Fellow

Dr. Li obtained MD from Tongji Medical University. She joined Dr. Zhang’s laboratory in 2014 at Virginia Commonwealth University. In 2018, she moved to Wayne State University with the lab. She has been studying the role of MEIG1/PACRG complex  in spermatogenesis.

Candice(Yi Tian) Yap – Ph. D Student

Candice received her BSc (Hons) in Biomedical Sciences from the University of Nottingham, UK in 2016. She then worked as an embryologist in a private fertility clinic, specializing in both clinical andrology and embryology skills including intracytoplasmic sperm injection (ICSI) and oocyte and sperm cryopreservation. Candice joined Dr. Zhibing Zhang’s lab in 2018 as a PhD student. She is currently studying the roles of various Intraflagellar Transport (IFT) genes in spermatogenesis and the contribution of transcriptional regulation on the expression levels of IFT genes.

Qi Zhou – Graduate Student

Qi Zhou graduated from Hubei University of Traditional Chinese Medicine in China and now she is studying for a master’s degree at Wuhan University of Science and Technology.  In September 2019, she came to Professor Zhang’s laboratory as a visiting scholar.  The role of ITF in spermatogenesis that she is currently studying.

1. Shuo Yuan, Yitian Yap, Cassidy Wood, Qian Huang, Ling Zhang, Zhibing Zhang, Yunhao Liu.         Dissecting the SPAG6 domain that mediates interaction with Snapin. Mol Reprod Dev. In press

2. Zhang L, Zhen JK, Huang Q, Liu H, Li W, Zhang SY, Min J, Li YH, Shi K, Woods J, Chen XQ, Shi  YQ, Liu Y, Hess RA, Song S, Zhang Z.  Mouse spermatogenesis-associated protein 1 (SPATA1), an IFT20 binding partner, is an acrosomal protein.

Developmental Dynamics, 2019 Dec 9. doi: 10.1002/dvdy.141. [Epub ahead of print].

3. Wang Z, Shi Y, Ma S, Huang Q, Yap YT, Shi L, Zhang S, Zhou T, Li W, Hu B, Zhang L, Krawetz SA, Pazour GJ, Hess RA, Zhang Z*. Abnormal fertility, acrosome formation, IFT20 expression and localization in the conditional Gmap210 knockout mice.

 Am J Physiol Cell Physiol. 2019 Oct 2. doi: 10.1152/ajpcell.00517.2018. [Epub ahead of print] PMID: 31577511. * Corresponding author.

4. Xiong W, Zhang L, Liu H, Li N, Du Y, He H, Zhang Z, Liu Y. E2 -mediated EMT by activation of β-catenin/Snail signalling during the development of ovarian endometriosis.

J Cell Mol Med. 2019 Sep 27. doi: 10.1111/jcmm.14668. PMID: 31560827.

5. Huang Q, Liu H, Zeng J, Li W, Zhang S, Zhang L, Song S, Zhou T, Sutoysky M, Sutoysky P, Pardi  R, Hess RA, Zhang Z*. COP9 signalosome complex subunit 5, an IFT20 binding partner, is essential to maintain male germ cell survival and acrosome biogenesis.

 Biol Reprod. 2019 Aug 2.pii: ioz154.  doi:10.1093/biolre/ioz154.  [Epub ahead of print]   PMID:31373619. * Corresponding author.

6. Liu Y, Zhang L, Li W, Huang Q, Yuan S, Li Y, Liu J, Zhang S, Pin G, Song S, Ray PF, Arnoult C, Cho C, Garcia-Reyes B, Knippschild U, Strauss III JF, Zhang Z*. The sperm associated antigen 6 interactome and its role in spermatogenesis.

Reproduction. 2019 May 1. pii: REP-18-0522.R1. doi: 10.1530/REP-18-0522. [Epub ahead of print].  PMID:31146259. * Corresponding author.

7. Shi L, Zhou T, Huang Q, Zhang S, Li W, Zhang L, Hess RA, Pazour GJ, Zhang Z*.  Intraflagellar transport protein 74 is essential for spermatogenesis and male fertility in mice.

Biol Reprod. 2019 Apr 20. pii: ioz071. doi: 10.1093/biolre/ioz071. * Corresponding author. PMID: 31004481.

8. Zhang Z, Huang Q, Wang Z, Zou J, Yu Z, Strauss JF, Zhang Z*.  Elongin B is a binding partner of the male germ cell nuclear speckle protein sperm-associated antigen 16S (SPAG16S) and is regulated post-transcriptionally in the testis.

Reprod Fertil Dev. 2019 Feb 28. doi: 10.1071/RD18303. Cover paper.  * Corresponding author. PMID: 30811962.

9. Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y, Xiong X.   Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis.

J Cell Mol Med.  2019 Jan; 23(1):439-452. doi: 10.1111/jcmm.13947.  PMID: 30324652. Collaborator.

10. Du Y, Zhang Z, Xiong W, Li N, Liu H, He H, Li Q, Liu Y, Zhang L. Estradiol promotes EMT in endometriosis via MALAT1/miR200s sponge function.

Reproduction. 2018 Nov 1. pii: REP-18-0424.R2. doi: 10.1530/REP-18-0424. PMID: 30500775. Collaborator.

11. Liu H, Du Y, Zhang Z, Lv L, Xiong W, Zhang L, Li N, He H, Li Q, Liu Y. Autophagy contributes to hypoxia-induced epithelial to mesenchymal transition of endometrial          epithelial cells in endometriosis. ​​​​​​​

Biol Reprod. 2018 Nov 1; 99(5): 968-981. doi: 10.1093/biolre/ioy128. PMID: 29860279. Collaborator.

12. Kazarian E, Son H, Sapao P, Li W, Zhang Z, Strauss JF, Teves ME.  SPAG17 Is Required for Male Germ Cell Differentiation and Fertility.

Int J Mol Sci. 2018 Apr 21;19(4). pii: E1252. doi: 10.3390/ijms19041252. PMID: 29690537. Collaborator.

13. Zhang Y, Liu H, Li W, Zhang ZG, Zhang S, Teves ME, Stevens C, Foster JA, Gregory E Campbell GE, Windle JJ, Hess RA, Pazour GL Zhang Z*.  Intraflagellar Transporter Protein IFT140 Is Essential For Spermiogenesis In Mice.

Cytoskeleton.  2018.75(2): 70-84. Cover paper. * Corresponding author. PMID: 29236364.

14. Li W, Miner AS, Zhang L, Ratz P, Zhang Z*. Mouse meiosis expressed gene 1 is not phosphorylated in vivo.

Mol Reprod Dev. 2018. 85(4): 288-289. * Corresponding author. PMID: 29393537.

15. Zhang Y, Liu H, Li W, Zhang ZG, Shang X, Zhang D, Li Y, Zhang S, Liu J, Hess RA, Pazour GL, Zhang Z*.   Intraflagellar Transporter Protein (IFT27), an IFT25 binding partner, Is Essential For Male Fertility and Spermiogenesis In Mice.

Developmental Biology.  2017. 432(1): 125-139. * Corresponding author. PMID: 28964737.

16. Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y, Liu Y. Hypoxia-inducible factor-1α promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis.

Reproduction. 2017 Jun; 153(6): 809-820. PMID: 28348069. Collaborator.

17. Liu H, Li W, Zhang Y, Zhang ZG, Shang X, Zhang L, Li Y, Somoza AV, Delpi B, Foster JF, Hess RA, Pazour GJ, Zhang Z. IFT25, an intraflagellar transporter protein dispensable for ciliogenesis in somatic cells, is essential for sperm flagella formation.

Biol Reprod. 2017 Apr 18.96:993-1006. Cover paper, * Corresponding author. PMID: 28430876.

18. Zhang L, Xiong W, Li N, Liu H, He H, Du Y, Zhang Z, Liu Y. Estrogen stabilizes hypoxia inducible factor 1α through G protein coupled estrogen receptor in eutopic endometrium of endometriosis.

Fertil Steril. 2017 Feb; 107(2): 439-447. PMID: 27939762. Collaborator.

19. Zhang L*, Liu Y, Li W, Zhang Q, Li Y, Liu J, Min J, Shuang C, Song S, Zhang Z*. Transcriptional regulation of Sperm associated antigen 16 by S-SOX5.

BMC molecular Biol. 2017; 18(1): 2. doi: 10.1186/s12867-017-0082-3.  * Co-corresponding author.  PMID: 28137312.