Cited by 989
University of Vermont
Publishes on Lysosomal Storage Disorders Research, Neurogenesis and neuroplasticity mechanisms, Glycosylation and Glycoproteins Research. 210 papers and 11.4k citations.
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Interleukin-1beta (IL-1beta) is a proinflammatory cytokine associated with the pathophysiology of demyelinating disorders such as multiple sclerosis and viral infections of the CNS. However, we demonstrate here that IL-1beta appears to promote remyelination in the adult CNS. In IL-1beta(-/-) mice, acute demyelination progressed similarly to wild-type mice and showed parallel mature oligodendrocyte depletion, microglia-macrophage accumulation, and the appearance of oligodendrocyte precursors. In contrast, IL-1beta(-/-) mice failed to remyelinate properly, and this appeared to correlate with a lack of insulin-like growth factor-1 (IGF-1) production by microglia-macrophages and astrocytes and to a profound delay of precursors to differentiate into mature oligodendrocytes. Thus, IL-1beta may be crucial to the repair of the CNS, presumably through the induction of astrocyte and microglia-macrophage-derived IGF-1.
Mammalian sulfoglycolipids comprise two major members, sulfatide (HSO3-3-galactosylceramide) and seminolipid (HSO3-3-monogalactosylalkylacylglycerol). Sulfatide is a major lipid component of the myelin sheath and serves as the epitope for the well known oligodendrocyte-marker antibody O4. Seminolipid is synthesized in spermatocytes and maintained in the subsequent germ cell stages. Both sulfoglycolipids can be synthesized in vitro by using the isolated cerebroside sulfotransferase. To investigate the physiological role of sulfoglycolipids and to determine whether sulfatide and seminolipid are biosynthesized in vivo by a single sulfotransferase, Cst-null mice were generated by gene targeting. Cst(-/-) mice lacked sulfatide in brain and seminolipid in testis, proving that a single gene copy is responsible for their biosynthesis. Cst(-/-) mice were born healthy, but began to display hindlimb weakness by 6 weeks of age and subsequently showed a pronounced tremor and progressive ataxia. Although compact myelin was preserved, Cst(-/-) mice displayed abnormalities in paranodal junctions. On the other hand, Cst(-/-) males were sterile because of a block in spermatogenesis before the first meiotic division, whereas females were able to breed. These data show a critical role for sulfoglycolipids in myelin function and spermatogenesis.