Damage to the central nervous system (CNS) is tragically difficult to restore: the numerous types of neurons are postmitotic, and in most CNS regions their loss is permanent. The discovery that neural stem cells generate neurons in the embryo and in a few regions in the adult raises the possibility that they can be harnessed to generate new neurons for CNS repair. The long-term objective of these studies is to understand how CNS stem cells generate different neuron types, and how this can be applied clinically. Currently, we know little about the neuron types stem cells generate. In the normal adult, neurogenesis is limited to interneuron production, and it is not known whether adult stem cells can make the variety of projection neurons born during embryogenesis and early development. The neuron types that stem cells are capable of generating at different stages - their developmental potential - needs to be elucidated. In addition, the plasticity of neural stem cells - what neuron types they produce after transplantation into different stages or regions of the CNS and into the damaged CNS - needs evaluation. These issues remain unresolved largely because of the difficulty in isolating these rare cells to permit study of an identified, fresh stem cell population. Unfortunately, culture-expanded stem cells largely generate gila after transplantation in vivo. Recently we discovered that the carbohydrate LeX is expressed on the surface of cortical stem cells throughout life. We can now acutely isolate neural stem cells from different stages using FACS and analyze their developmental potential and plasticity. This will be done using clonal culture analysis, which provides information about the types of progeny an individual stem cell generates. In addition, we will implant these stem cells into the embryonic brain in vivo to reveal what neurons they produce in a developing system. Fresh stem cells will also be implanted into a model of ischemic damaged cerebral cortex to assess whether they can generate appropriate neuron types after CNS damage. Given LeX is expressed by all neural stem cells, we will examine its role by up and down regulating expression of the LeX-synthesizing enzymes FucT4 and FucT9 and assessing neural stem cell behavior. Because LeX is extremely abundant in embryonic regions expressing FGF-8 and Wnts, we will examine the impact of these growth factors on neural stem cells.
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