Zhibing Zhang, M.D.

The research in my laboratory focuses on studying mechanisms of mammalian spermatogenesis. Mouse meiosis expressed gene 1 (Meig1) was originally cloned in an effort to search genes essential for mouse meiosis. I identified this gene in a yeast two-hybrid screen using mouse sperm associated antigen 16 (Spag16) as the bait. Mouse Spag16 is a dual functional gene; the translated protein products not only regulate sperm motility but also control spermatogenesis.

Unexpectedly, Meig1 knockout mice showed severe spermiogenesis defects instead of meiosis defects. MEIG1 is expressed in the cell bodies of spermatocytes and round spermatids but is recruited to the manchette in elongating spermatids by PACRG, another key spermiogenesis regulator. The manchette is a unique structure only present in elongating spermatids. One of the proposed functions of the manchette is to transport cargo proteins by intra-manchette transport (IMT) for sperm tail formation. The manchette is disrupted in the Meig1 knockout mice.

Our studies highlight the role of MEIG1/PACRG complex in modulating manchette function. Thus, one of the goals in my career is to investigate the mechanism of the novel MEIG1/PACR complex in IMT for normal spermiogenesis, sperm flagella formation and male fertility.

Even though the Meig1 gene is expressed in both germ cells and somatic cells, the global Meig1 knockout mice only showed a male infertility phenotype; thus, MEIG1 is an ideal target for developing a male-based contraceptive drug. Identifying the specific amino acids that are essential for the function of the complex will help in the design small molecules that block interactions between MEIG1/PACRG and its binding partners and therefore interfere with spermiogenesis. Collaborating with structural scientists at Virginia Commonwealth University, we resolved MEIG1 structure by nuclear magnetic resonance (NMR).

We wish to further determine the PACRG structure and to explore the structural basis for MEIG1/PACRG complex formation and to investigate the role of MEIG1/PACRG interaction in mouse fertility and spermiogenesis in vivo. In addition, we discovered that MEIG1/PACRG associates with a motor system localized in the manchette.

Therefore, I not only wish to develop a male-based contraceptive drug, but also propose to a cargo (SPAG16)-chaperone (MEIG1/PACRG)-motor transport system in the manchette for sperm flagella formation.