Molecular mechanisms regulating subventricular zone progenitor migration

点击翻译按钮获取中文摘要

The large majority of our nerve cells are generated during fetal development. However, two regions of the brain contain stem cells and continuously make hundreds of thousands of new nerve cells throughout life. My laboratory has actively studied these stem cells and the nerve cells they make for over twenty years. One of the regions, the subependymal zone (SEZ), makes nerve cells that migrate long distances. They move from the SEZ to a brain region called the olfactory bulb which has to do with the sense of smell. When we experimentally inhibit the migration, the newborn nerve cells whither and die and olfaction diminshes. There are many unsolved questions surrounding SEZ nerve cell migration. The answers are vital to discover as proper migration is fundamental for brain function. When migration goes wrong, brain malformations can arise in the embryo and lead to neurological problems such as mental retardation and epilepsy. Migration is a dynamic process best visualized and understood in real-time; we developed a powerful 2-photon time-lapse microscope that detects nerve cell migration deep in tissue without damaging it. Our microscope employs lasers that pulse incredibly rapidly to generate three-dimensional images of fluorescently labeled cells, which we then reconstruct into movies. Using advanced software, we track cell positions and thus generate rich and detailed information on cell movement. We recently discovered that a protein called galectin-3 (Gal-3) specifically regulates SEZ nerve cell migration. Our novel finding was fascinating because Gal-3 was known to affect cancer and inflammation but not normal brain processes. Although Gal-3 was known in brain injury, our work proved that it also works in the healthy brain. In fact, Gal-3 was found only in the SEZ, and no other brain region. Gal-3 frequently "multi-tasks": in addition to migration, it can also regulate cell division and survival. We found such effects of Gal-3 do not occur in the SEZ; it was only important for migration. Although we showed Gal-3 regulates migration, the specific way in which it does so is unclear. In this project we seek to discover the ways Gal-3 regulates nerve cell movement. 1) We will test how much it promotes adhesion of SEZ cells. We believe Gal-3 interacts with other proteins to maintain the right level of adhesion between cells. Too much adhesion causes cells to get stuck and not move; too little adhesion and they will not have the traction needed for motility. We will also test how much Gal-3 mediated adhesion causes shifts from individual cell migration to group migration. 2) We will test whether Gal-3 regulates motile cilia and the establishment of these road maps. Gal-3 was expressed on SEZ cells with motile cilia, small whip-like protrusions that cause brain fluid (cerebrospinal fluid) flow. The fluid flow creates molecular gradients, which form a road map for nerve cells to migrate in the right direction. 3) We will next test if Gal-3 regulates migration by interacting with another protein called epidermal growth factor receptor (EGFr). We showed EGFr is important for SEZ nerve cell migration and that it is controlled by Gal-3. 4) Finally, we will test if Gal-3's cousin, Gal-1, interacts with it to regulate nerve cell migration. This last experiment is important since Gal-1 regulates SEZ proliferation but its function in migration remains untested.By defining the molecular regulation of nerve cell migration, this project will fill a big gap in the understanding of the overall process of adult nerve cell production. Cell migration is a general feature of embryonic development and is also relevant for the adult immune system's normal function and in cancer. Therefore the insights gleaned from these studies are predicted to be of multiple interest and applicable to biologists in research and clinicians in practice.