Zhibing Zhang, M.D., Ph.D.
Department of Obstetrics/Gynecology
Office/Laboratory: Sanger hall: 11-004, 11-008
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.
1. Dissection of the structural base of MEIG1/PACRG complex in assembling sperm flagella;
2. The role of intraflagellar transport proteins in mammalian spermatogenesis;
3. Novel functions of mammalian central apparatus proteins, their roles in microtubule/cytoskeleton
system and tumorigenesis.
4. Transcriptional and post-transcriptional regulation of genes in ciliogenesis/spermatogenesis.
Knockout and transgenic animal models, cell culture, confocal microscopy, microarrays, transcriptional regulation of gene expression, etc.
NIH 1RO1HD076257: Dissection of the structural basis of MEIG1 in assembling sperm flagella
NIH 1R03HD090306-01: The role of transcription factor S-SOX5 in male fertility and sperm flagella formation
- Zhang Z*, Shen X, Gude D, et al. MEIG1 is essential for spermiogenesis in mice. Proc Natl Acad Sci USA. 2009, 106(40): 17055-60. * Corresponding author.
Kiselak EA, Shen X, Song J, Gude DR, Wang J, Brody SL, Strauss JF 3rd, Zhang Z*. Transcriptional regulation of an axonemal central apparatus gene, sperm-associated antigen 6, by a SRY-related high mobility group transcription factor, S-SOX5. J Biol Chem. 2010, 285(40): 30496-505. * Corresponding author.
Li W, Tang W, Teves ME, Ling Zhang, Archer KJ, Williams Jr DC, Peterson DL, Strauss JF, Zhang Z*. A MEIG1/PACRG complex in the manchette is essential to transport structural proteins to build sperm flagella. Development. 2015; 142(5): 921-30. * Corresponding author.
Li W, Mukherjee A, Wu J, Zhang L, Li H, Teves ME, Strauss JF, Fang X, Zhang Z*. Mouse Sperm Associate Antigen 6 Regulates Cell Growth, Cell Migration And Ciliogenesis Through Activation of Acetylated Tubulin In Mouse Embryonic Fibroblast Cells. Sci Reps. 2015; 5:16506. * Corresponding author.
Li W, Walavalkar NM, Teves ME, Zhang L, Liu J, Peterson D, Strauss JF, Williams Jr DC*, Zhang Z*. Dissecting the structural basis of MEIG1 interaction with PACRG. Sci Reps. 2016. 6:18278. * Co-corresponding authors.
- Wei Li: Post-doc
Hong Liu: Technician
Andres V Somoza: Undergraduate student