Sphingoglycolipids of normal and pathological brains

The long-term goal of this project is to elucidate the functional roles of glycosphingolipids (GSLs), particularly gangliosides, during normal nervous system development and under pathological conditions. These molecules are abundant in the nervous system and are primarily localized on the plasma membrane surface. Dramatic, consistent changes in ganglioside expression are observed during neurogenesis and maturation, particularly during the early stages of brain development. The primary localization of gangliosides on cell surface microdomains and the drastic quantitative and compositional changes during brain development strongly suggest that these GSLs are involved in modulating the fate regulation of neural stem cells (NSCs) and neural precursor cells (NPCs). A large body of knowledge has been firmly established regarding the expression of stage-specific GSL antigens on these cells and their role in neuronal migration and signal regulation. In this investigation, we will perform biochemical, cell biological, and molecular biological analyses to investigate the expression patterns of gangliosides, the involvement of gangliosides in neural cell fate determination, and the regulatory mechanisms of glycosyltransferases (GTs). We will focus on NSCs/NPCs because these cells have already committed to neural cell lineage differentiation and are capable of further differentiating into various cell types in response to such developmental cues as cytokines and growth factors. Our studies will be focused on the following two specific aims: (1) Elucidation of the functions of gangliosides in regulation of NSC/NPC cell fate determination, such as self-renewal, proliferation, differentiation, migration, and survival, (2) Characterization of the post-translational regulatory mechanisms of GTs responsible for the dramatic changes of ganglioside expression during NPC differentiation. At present, very few systematic studies have been done in the glycobiology of NSCs/NPCs. The research proposed here is intended to fill this gap. An understanding of the molecular mechanisms underlying the differential expression of cell surface gangliosides should greatly enhance our knowledge of their function in normal brain development and in developmental disorders that result in mental retardation.