Abstract
The article by Zhou and colleagues in this issue of Blood highlights the importance of Notch glycosylation in suppression of myelogenesis.
The extracellular domain of all 4 mammalian Notch receptors contains 29 to 36 epidermal growth factor (EGF)–like repeats, many of which are predicted to be modified with 2 unusual carbohydrates: O-linked fucose and O-linked glucose. Work in a number of laboratories has revealed that O-fucosylation is essential for Notch function in many contexts,1 and a recent report has shown that O-glucosylation is essential for Notch function in Drosophila.2 In addition, elongation of O-fucose by members of the Fringe family of β1,3-N-acetylglucosaminyltransferases modulates Notch activity. Several years ago, Smith et al developed a mouse lacking a key enzyme in GDP-fucose biosynthesis (FX−/−).3 These mice lack all forms of fucosylation, including O-fucosylation of Notch, and do not survive long after birth unless fucose is added to their diet. A salvage pathway uses the fucose to rescue GDP-fucose biosynthesis, restoring fucosylation. In the absence of fucose, the FX−/− mice display a profound neutrophilia. Part of this neutrophilia can be explained by loss of selectin ligands (Sialyl Lewis x contains fucose), but proliferation of myeloid progenitor cells suggests that myelopoiesis is being stimulated. Zhou and coworkers have now examined the proliferation of myeloid lineages in FX−/− mice and attributed it to loss of fucose-dependent Notch activation in myeloid progenitors. The authors present compelling data that suggests a role for Notch activation in suppression of myeloid differentiation, a somewhat controversial area. Another recent publication highlighted the importance of O-fucose at a specific site on Notch1 in T-cell development.4 Ge and Stanley generated a mouse in which endogenous Notch1 was replaced with a mutant lacking the O-fucosylation site in the ligand-binding domain (within EGF repeat 12). Homozygotes developed fairly normally but had a reduced number of T cells, suggesting that O-fucosylation of Notch1 at EGF repeat 12 is important for T-cell development.
These results raise a number of interesting questions. All 4 receptors should be unfucosylated in FX−/− mice, but it is not known which Notch receptor is responsible for suppression of myeloproliferation. As mentioned, modification of O-fucose by Fringe modulates Notch activity. In the absence of Fringe, O-fucose remains a monosaccharide, but in the presence of Fringe it is elongated to a tetrasaccharide. The relevant structures of the O-fucose glycans that are lost in FX−/− mice are unknown. Because O-fucosylation of EGF repeat 12 in Notch1 plays such an important role in T-cell development, it would be interesting to know if loss of this specific fucose also suppresses myelogenesis. The future of Notch and hematopoiesis certainly looks sweet.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
REFERENCES
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