Qi's Laboratory

Male germ cells play vital functions during animal development. They carry half of genetic information of the animal species from generation to generation, activate eggs following fertilization and start the development of new life.  Following birth, male germ line stem cells, the foundation of spermatogenesis, undergo a series of complicated events, including mitosis, meiosis and cellular morphogenesis, eventually give rise to matured male gamete - sperm. Abnormalities that occur during these events in human can cause reproductive diseases and affect health. Research on male germ cells can thus not only solve fundamental questions in developmental biology but also provide means for clinical applications. Using mouse as a model system, we wish to understand molecular mechanisms that govern spermatogenesis: what are the determining factors and molecular mechanisms that regulate the developmental program of male germ cells? Research in the lab include: 

1) Regulation of self-renewal and differentiation of spermatogonial stem cells. Mouse spermatogonial stem cells support the life-long generation of male gamete – sperm. Although not as well studied as the germ-line stem cells in lower species, such as Drosophila, mouse spermatogonial stem cells have been an ideal model system for the study of stem cell biology and germ cell development in past decades. Many questions remain to be fully addressed.  What are the molecular signatures of mammalian spermatogonial stem cells?  How are their pluripotency maintained by signals emitted from specific niche environment during their self-renewal and proliferation? Using transgenic mouse model, we purified spermatogonial stem cells from post-natal mice and analyzed their global gene expression profiles during development. This type of comparative gene expression studies suggests that changes in global gene expression occur during the establishment of spermatogonial stem cells (from their precursor cells – gonocytes) and differentiation. Various genes are highly enriched in spermatogonial stem cells, comparing to earlier stage gonocytes and differentiated spermatogenic cells. Using molecular and cell biological approaches, including in situ hybridization, in vitro cell culture, as well as mouse genetics, we are analyzing expression patterns of specific genes in spermatogonial stem cells and these genes’ biological functions.

2) Mouse spermiogenesis. Spermatogenesis in mouse encompassing three consecutive stages: mitosis, meiosis and cell morphogenesis. The last stage, also called spermiogenesis, occurs when spermatocytes complete meiosis and enter the post-meiotic development during which round, haploid spermatids are transformed into mature, whip-like spermatozoa with biological functions. The morphogenesis of spermatids includes numerous cellular changes such as nuclear condensation, acrosome formation and flagella formation. This process is regulated on both transcriptional and translational levels. Due to the chromatin structure changes and nuclear condensation, haploid spermatids have limited gene transcription activity. Proteins required for the cellular morphogenesis are synthesized from both pre-stored and newly made messengers. The post-transcriptional and translational regulations are thus the main regulatory mechanisms that govern the maturation of spermatozoa. Through the analyses of sperm specific protein AKAP3 (a kinase anchoring protein 3), we find that multiple RNA binding proteins and PKA signaling pathway play important roles in regulating gene expression during spermiogenesis. RNA binding protein complex(es) and PKA signaling may participate in the regulation of messenger RNAs and influence protein translational activities in response to environmental stimuli during the elongating stage of spermiogenesis. Combining biochemical, cellular and molecular approaches, we are dissecting the relationships among the RNA binding proteins and mechanisms by which signaling pathways participate in the sperm development.

3) One of the highly debated questions in stem cell and developmental biology is that whether the cell fate of a particular cell type (like germ cells) can be differentiated and manipulated in an in vitro system. Germ cells have the characteristics of being both highly differentiated and maintaining the reprogramming potential at the same time. What are the factors that allow germ cells to maintain reprogramming potency? Can the knowledge we gain from studying spermatogenesis facilitate the in vitro differentiation of male germ cells from stem cells? We are also conducting experiments using in vitro cell culture system to differentiate male germ cells from pluripotent embryonic stem cells.