Gangliosides, abundant in the nervous system, are known to play crucial modulatory roles in cellular recognition, interaction, adhesion, and signal transduction, particularly during early developmental stages. The expression of gangliosides in the nervous system is cell specific and developmentally regulated, and closely related to the differentiation state of the cell. We hypothesize that the temporal and spatial expression of gangliosides in the nervous system is closely related to the neural differentiation, including neuronal migration and neuron/axon interaction, and that their expression is tightly regulated by their metabolism, in particular, biosynthesis. Taking advantage of the recent advances in the embryonic stem (ES) cell field, we will examine the differential expression, metabolism, and regulatory mechanisms of these important glycoconjugates during various stages of cellular differentiation. To better understand the metabolic basis of the ganglioside expression, we will focus on the subcellular localization, intracellular trafficking, and regulatory mechanisms of the expression of several key glycosyltransferases (GTs), particularly GM3-synthase (ST-I), GD3-synthase (ST-II), and GM2/GD2-synthase (GalNAcT), that regulate the synthesis of gangliosides along different pathways. To achieve these goals, three specific aims are proposed to examine the following aspects of their regulation.
Aim 1. Regulation of ganglioside expression during neural development, a. Characterization of stage- and cell-specific GSL markers in differentiating ES cells and ganglioside knockout ES cells; b. Characterization of the functional role of gangliosides in neuronal migration.
Aim 2. Transcriptional regulation of GTs in differentiating neural cells, a. Characterization of the promoter and enhancer elements the GT genes, b. Characterization of the transcription factors that interact with the promoter/enhancer elements of these genes during ES cell differentiation.
Aim 3. Post-translational modification of enzymes for ganglioside biosynthesis--Intracellular localization, trafficking, and complex formation of GTs in differentiating ES cells. An understanding of the molecular mechanisms underlying the differential expression of cell surface gangliosides should greatly enrich our knowledge of their functions in normal brain development and developmental disorders that result in mental retardation. ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS011853-31
Application #
6919878
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Owens, David F
Project Start
1988-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
31
Fiscal Year
2005
Total Cost
$339,625
Indirect Cost
Name
Georgia Health Sciences University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Itokazu, Yutaka; Wang, Jing; Yu, Robert K (2018) Gangliosides in Nerve Cell Specification. Prog Mol Biol Transl Sci 156:241-263
Itokazu, Yutaka; Tsai, Yi-Tzang; Yu, Robert K (2017) Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J 34:749-756
Tsai, Yi-Tzang; Itokazu, Yutaka; Yu, Robert K (2016) GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells. Neurochem Res 41:107-15
Yu, Robert K; Usuki, Seigo; Itokazu, Yutaka et al. (2016) Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro. Glycobiology 26:63-73
Koon, Noah A; Itokazu, Yutaka; Yu, Robert K (2015) Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice. ASN Neuro 7:
Itokazu, Yutaka; Yu, Robert K (2014) Amyloid ?-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol Neurobiol 50:186-96
Usuki, Seigo; O'Brien, Dawn; Rivner, Michael H et al. (2014) A new approach to ELISA-based anti-glycolipid antibody evaluation of highly adhesive serum samples. J Immunol Methods 408:52-63
Parameswaran, Reshmi; Lim, Min; Arutyunyan, Anna et al. (2013) O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia. J Exp Med 210:805-19
Wang, Jing; Yu, Robert K (2013) Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro. Proc Natl Acad Sci U S A 110:19137-42
Ariga, Toshio; Itokazu, Yutaka; McDonald, Michael P et al. (2013) Brain gangliosides of a transgenic mouse model of Alzheimer's disease with deficiency in GD3-synthase: expression of elevated levels of a cholinergic-specific ganglioside, GT1a?. ASN Neuro 5:141-8

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