Genetic analysis of myelin galactolipid function

Approximately 70% of the dry weight of myelin is lipid, with the galactolipid galactocerebroside (GalC) and its sulfated derivative sulfatide encompassing about one-third of the lipid mass (reviewed by Norton and Cammer, 1984), This abundance, along with the results of a number of antibody perturbation studies, led to the hypothesis that the galactolipids play an important role in the formation and maintenance of the myelin sheath (reviewed by Dyer, 1993; Coetzee et al., 1998; Dupree et al., 1998b; Stoffel and Bosio, 1997). The isolation of the gene that encodes UDP-galactose:ceramide galactosyltransferase (CGT) (Schulte and Stoffel, 1993; Stahl et al., 1994; Schaeren-Wiemers et al., 1995), the enzyme which catalyzes the final step in the synthesis of GalC (Morell and Radin, 1969), enabled the genetic analysis of galactolipid function. In particular, Coetzee et al. (1996b) and Bosio et al. (1996) used the gene targeting approach in embryonic stem cells to generate mice with a null mutation in the CGT gene. In this chapter we will review the results of the detailed biochemical and ultrastructural analyses of these mutant animals and provide a summary of the current hypothesis concerning the function of galactolipids in the myelination process.