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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM084135-06A1
Application #
8628360
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Gaillard, Shawn R
Project Start
2008-04-01
Project End
2017-12-31
Budget Start
2014-01-17
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$297,350
Indirect Cost
$107,350
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Harvey, Beth M; Rana, Nadia A; Moss, Hillary et al. (2016) Mapping Sites of O-Glycosylation and Fringe Elongation on Drosophila Notch. J Biol Chem 291:16348-60
Servián-Morilla, Emilia; Takeuchi, Hideyuki; Lee, Tom V et al. (2016) A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 8:1289-1309
Thakurdas, Shakeel M; Lopez, Mario F; Kakuda, Shinako et al. (2016) Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63:550-65
Haltom, Amanda R; Jafar-Nejad, Hamed (2015) The multiple roles of epidermal growth factor repeat O-glycans in animal development. Glycobiology 25:1027-42
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

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