Glial cells have a profound influence on neuronal functions. Oligodendrocytes and Schwann cells ensheath axons with myelin to enable rapid nerve impulse conduction. Astrocytes support neurons in multiple ways, and also influence synaptic development and function. A variety of signals are transmitted between neurons and glia. The transmission and reciprocal exchange of these signals are based on the contact or close apposition of neuronal and glial cell elements. Thus one of the key questions in the field of neuron-glia interactions is how these intricate spatial arrangements are established during development and how they are maintained in the adult nervous system. This program project aims to understand the role of three groups of molecules, namely heparan sulfate proteoglycans, the NG2 chondroitin sulfate proteoglycan, and ephrin-A/EphA cell contact-dependent signaling molecules, in the establishment and maintenance of neuronglia communication. These three groups of molecules have a strong involvement in the development and differentiation of glial cell types. The investigators'preliminary data further implicate them in various types of neuron-glia interactions. Projects I and II investigate the role of glial proteoglycans, heparan sulfate proteoglycans, and the NG2 chondroitin sulfate proteoglycan, respectively, on Schwann cell and oligodendrocyte development and myelination. Project III focuses on the role of ephrin/Eph proteins in the cell surface interactions between dendritic spines and perisynaptic astrocytes to elucidate molecular mechanisms of neuron-glia crosstalk at synapses. While the three projects investigate different families of molecules in different cellular systems, they share the same basic research strategy, combining in vivo analysis of mutant mice with in vitro analysis of primary cell cultures derived from mutant mice. This strategy will allow direct comparison of the in vivo consequences of ablating a given molecule and the behavior of mutant cells in vitro for each of the three molecular groups. Extensive collaborations within the program will produce synergistic achievements more widely applicable to neuron-glia interactions in general. Furthermore, the program will explore new lines of research at the interfaces among component projects, and obtain answers to important questions beyond the immediate reaches of each component. This program project will impact the understanding of molecular and cellular crosstalk by which neurons and glial cells establish and maintain neuron-glia communication, providing molecular insight into demyelinating diseases and neurological disorders in which the disruption of neuron-glia communication is an initiating factor.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD025938-19
Application #
7763940
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Henken, Deborah B
Project Start
2007-03-10
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
19
Fiscal Year
2010
Total Cost
$1,476,164
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yotsumoto, Fusanori; You, Weon-Kyoo; Cejudo-Martin, Pilar et al. (2015) NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization. Oncoimmunology 4:e1001204
Arranz, Amaia M; Perkins, Katherine L; Irie, Fumitoshi et al. (2014) Hyaluronan deficiency due to Has3 knock-out causes altered neuronal activity and seizures via reduction in brain extracellular space. J Neurosci 34:6164-76
Vargas, Lina M; Leal, Nancy; Estrada, Lisbell D et al. (2014) EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-? oligomers. PLoS One 9:e92309
You, Weon-Kyoo; Yotsumoto, Fusanori; Sakimura, Kenji et al. (2014) NG2 proteoglycan promotes tumor vascularization via integrin-dependent effects on pericyte function. Angiogenesis 17:61-76
Cattaruzza, Sabrina; Ozerdem, Ugur; Denzel, Martin et al. (2013) Multivalent proteoglycan modulation of FGF mitogenic responses in perivascular cells. Angiogenesis 16:309-27
Tigges, Ulrich; Komatsu, Masanobu; Stallcup, William B (2013) Adventitial pericyte progenitor/mesenchymal stem cells participate in the restenotic response to arterial injury. J Vasc Res 50:134-44
Falivelli, Giulia; Lisabeth, Erika Mathes; Rubio de la Torre, Elena et al. (2013) Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands. PLoS One 8:e81445
Noberini, Roberta; Koolpe, Mitchell; Lamberto, Ilaria et al. (2012) Inhibition of Eph receptor-ephrin ligand interaction by tea polyphenols. Pharmacol Res 66:363-73
Gibby, Krissa; You, Weon-Kyoo; Kadoya, Kuniko et al. (2012) Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan. Breast Cancer Res 14:R67
You, Weon-Kyoo; Bonaldo, Paolo; Stallcup, William B (2012) Collagen VI ablation retards brain tumor progression due to deficits in assembly of the vascular basal lamina. Am J Pathol 180:1145-58

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