Sphingolipids are key mediators and regulators of cell signaling pathways. Our studies have focused on the actions of two classes of sphingolipids represented by glycosphingolipids (GSLs) and sphingosine-1-phosphate (S1P). Our work is aimed at defining the normal functions of these sphingolipids and understanding their roles in disease processes. GSLs are found in the outer leaflet of the plasma membrane and are concentrated in specialized signaling structures. They are particularly abundant in neuronal cells in the form of gangliosides (sialic acid containing GSLs). Through genetic disruption of genes that encode synthetic enzymes for GSLs, we have created a series of mice that express limited glycosphingolipid structures. We are using these mice to discover the functions of GSLs. When the cellular machinery responsible for GSL degradation is defective, GSL storage diseases result in which profound neurodegeneration occurs. Examples are Tay-Sachs, Sandhoff and Gaucher diseases. S1P is a signaling molecule that is crucial for the regulation of several diverse cellular events, including cell survival, growth, differentiation and calcium mobilization. Recently, numerous studies on S1P have demonstrated its importance in the development of the cardiovascular system and immunity through a family of G protein-coupled receptors (GPCRs), designated S1P1-5. 1. We have shown that S1P also plays a key role in neural development, probably mediated by the S1P1 receptor. We found that simultaneous disruption of the two known sphingosine kinase genes in mice results in a deficiency of S1P, which disturbed angiogenesis and caused neural tube closure defects, followed by embryonic lethality. Dramatic increases in apoptosis and decreases in mitosis were seen in the developing nervous systems of these mutant embryos. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings not only provide new biological insights into S1P signaling, but also suggest that exploitation of this pathway could lead to the development of novel therapeutic approaches for neurological disease. 2. We have now established a Ugcg allele in mice flanked by loxP sites (floxed). When cre recombinase was expressed in the nervous system under the Nestin promoter, the floxed gene underwent recombination, resulting in a substantial reduction of Ugcg expression and of glycosphingolipid ganglio-series levels. The mice lacking Ugcg in the nervous system show a striking loss of Purkinje cells and abnormal neurologic behavior. The floxed Ugcg allele will facilitate the analysis of the function of glycosphingolipids in normal physiology and in diseases such as diabetes and cancer.
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