Notch signaling in an evolutionarily conserved pathway that regulates diverse processes in animals, including stem cell maintenance, cell fate specification, learning and memory, and angiogenesis. Maintaining an optimal level of Notch signaling is essential for normal human development and human health, as mutations that result in increased or decreased activity of the Notch pathway cause a number of human diseases, including cancer and developmental disease. Moreover, therapeutic manipulation of the Notch pathway activity is of great interest in Notch-related diseases and in regenerative medicine. We have identified an evolutionarily conserved enzyme called Rumi, which adds O-linked glucose to specific EGF repeats of Notch receptors and regulates Notch signaling in both Drosophila and mammals. Our data indicate that the number and distribution of O-glucose residues on the Drosophila Notch determines the strength of Notch signaling over a wide range, and that mammalian Notch signaling is sensitive to Rumi gene dosage is specific contexts. Our preliminary data indicate that addition of one or two xylose residue to O-glucose by newly identified enzymes can further regulate Notch signaling. Our data strongly suggest that the level and distribution of O-glucose and its extended forms on Notch tightly regulate the strength of Notch signaling. We will elucidate the mechanisms underlying the fine-tuning of the Notch pathway by carbohydrates by using a combination of Drosophila genetics, cell-based signaling assays and biochemical experiments. In the long run, this project has the potential to establish tools to alter the activity of Notch signaling by manipulating the level of O-glucose and xylose on Notch proteins.

Public Health Relevance

Alterations in the activity of the Notch pathway cause important human diseases including cancer and developmental disorders. The proposed studies examine the role of glucose and xylose molecules in regulating the strength of Notch signaling.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Gaillard, Shawn R
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Baylor College of Medicine
Schools of Medicine
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LeBon, Lauren; Lee, Tom V; Sprinzak, David et al. (2014) Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states. Elife 3:e02950
Leonardi, Jessica; Jafar-Nejad, Hamed (2014) Structure-function analysis of Drosophila Notch using genomic rescue transgenes. Methods Mol Biol 1187:29-46
LeBon, Lauren; Lee, Tom V; Sprinzak, David et al. (2014) Correction: Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states. Elife 3:
Haltom, Amanda R; Lee, Tom V; Harvey, Beth M et al. (2014) The protein O-glucosyltransferase Rumi modifies eyes shut to promote rhabdomere separation in Drosophila. PLoS Genet 10:e1004795
Lee, Tom V; Sethi, Maya K; Leonardi, Jessica et al. (2013) Negative regulation of notch signaling by xylose. PLoS Genet 9:e1003547
Leonardi, Jessica; Fernandez-Valdivia, Rodrigo; Li, Yi-Dong et al. (2011) Multiple O-glucosylation sites on Notch function as a buffer against temperature-dependent loss of signaling. Development 138:3569-78
Takeuchi, Hideyuki; Fernandez-Valdivia, Rodrigo C; Caswell, Devin S et al. (2011) Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. Proc Natl Acad Sci U S A 108:16600-5
Fernandez-Valdivia, Rodrigo; Takeuchi, Hideyuki; Samarghandi, Amin et al. (2011) Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi. Development 138:1925-34
Jafar-Nejad, Hamed; Leonardi, Jessica; Fernandez-Valdivia, Rodrigo (2010) Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology 20:931-49
Lee, Tom V; Takeuchi, Hideyuki; Jafar-Nejad, Hamed (2010) Regulation of notch signaling via O-glucosylation insights from Drosophila studies. Methods Enzymol 480:375-98

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