Influence of glial cell line-derived neurotrophic factor (GDNF) on the male germ-line and its disruption by nanoparticles.

摘要

Spermatogenesis is a highly complex process that begins with a spermatogonial stem cell and ends with the production of mature sperm. This process is tightly regulated by the somatic cells, which provide the germ cells with the necessary growth factors for development. During spermatogenesis, the molecular mechanisms that determine whether a spermatogonial stem cell will self-renew or differentiate to produce a mature sperm cell still remain a mystery. One major obstacle that must be overcome to answer these questions is the development of an in vitro culture system that mimics the environment created by the somatic cells, which will allow these cells to be cultured for long periods of time.; The first study characterizes a spermatogonial stem cell line, the C18-4 cells, which were created by the lab, and the data indicates their usefulness in proliferation studies. The second study identifies the GFRalpha-1 receptor on the surface of the spermatogonial stem cells and their direct progeny. It also describes the role of GDNF, which is the ligand for the GFRalpha-1 receptor, in maintaining proliferation and differentiation in vitro. The third study focuses on identifying the signaling proteins that mediate the response to GDNF in the GFRalpha-1 positive spermatogonia. The fourth study examines how a growth factor can modulate another signaling pathway in the testes. The final study investigates the toxicity of silver-15nm, aluminum-30nm, and molybdenum oxide-30nm nanoparticles on germ cells versus somatic cells, and confirms that the germ-line is more sensitive to environmental assault than somatic cells.; Combined this research shows that there is an in vitro model system that can be used for studying spermatogonial stem cell proliferation, it also identifies a growth factor that will enhance culture conditions and allow stem cells to proliferate and differentiate, as well as identifying the signaling components responsible for the response to that growth factor. In addition, this study shows how a growth factor, such as GDNF, can modulate cell fate decisions. Lastly, the nanotoxicity studies demonstrate that the C18-4 stem cell line is a novel model for studying reproductive toxicity of the male germ-line.