Oligodendrocyte number and morphology are altered in transgenic mice lacking sulfatide

• Main Author: Shroff, Seema
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2008
• Subjects: Neurosciences
• ISBN: 9781109544244; 1109544243

The myelin galactolipid sulfatide is expressed at the onset of terminal differentiation of oligodendrocytes (OLs), is capable of transmembrane signaling, and is implicated in regulation of oligodendrocyte development as well as myelination. Although this lipid has been under extensive investigation for nearly 40 years, its precise function in OL differentiation and myelin formation remains elusive. In an attempt to clarify the role of sulfatide, we have used mice that are incapable of synthesizing this lipid. Based on our analysis of this mutant mouse, we provide strong in vivo evidence that sulfatide is not required for the differentiation of oligodendrocyte progenitor cells (OPCs) into OLs, or for the proper onset of myelination. However, sulfatide is essential for determining the final number of mature OLs that survive to adulthood and for sustaining the proper rate of myelin formation. Although we show that the rate of OL differentiation, as assessed by myelin gene and protein expression, is not altered in sulfatide null mice, adult sulfatide-deficient OLs maintain a morphologic phenotype consistent with active myelin production. This finding clearly demonstrates a disconnect between the antigenic and morphologic development of OLs. In the spinal cord of mice lacking sulfatide, we show that, although myelination is initiated correctly, progression of myelination is retarded, in spite of normal myelin gene expression and protein levels. Furthermore, we demonstrate the abnormal and persistent accumulation of myelin proteins and myelin-like inclusions in mature OL cell bodies which is suggestive of altered intracellular trafficking. Although wildtype (WT) and sulfatide null mice contain equal numbers of differentiated OLs at birth, there is a 50% increase in the number of mature OLs in the spinal cord of adult sulfatide null mice. No increase in the number of OPCs was noted, however, there is increased proliferation in the white matter tracts of the mutant mice and a significant decrease in OL apoptosis. Morphological analyses reveal that OLs lacking sulfatide extend 50% fewer processes than their WT siblings. Since axonal contact is an essential event for OPCs to avoid programmed cell death, OLs extending fewer processes is a plausible explanation for an enhanced cellular population. Thus, we conclude that although sulfatide null mice are initially normal, in terms of OL numbers, onset of OL differentiation, and initiation of myelin synthesis, these animals develop a deficit in myelination, possibly due to altered intracellular trafficking mechanisms.