The molecular interactions between axons and glial cells constitute an area of immense interest. Many diseases produce their debilitating effects by altering the structural and functional relations between axons and glial cells, which in turn affect action potential propagation and even neuronal survival. In vertebrate myelinated axons, a structural specialization, the axo-glial septate junction (SJ), forms at the paranode between myelin loops and the axonal surface. Axo-glial SJs are characterized by ladder-like electron dense structures. Our recent work shows that axo-glial SJs are also present in Drosophila nerves. In addition to structural similarities, compelling molecular homologies are observed between axo-. glial SJs in fly and those in mouse. The Drosophila proteins: Neurexin (NRX), Contactin (CONT) and Neuroglian (NRG) form a tripartite complex that localizes to axo-glial SJs. Their murine homologs NCP1, Contactin and Neurofascin 155kDa isoform (NF155) also form a complex at axo- glial SJs. Our phenotypic analyses of Drosophila neurexin and mouse NCP1 mutants show that both mutants lack SJs. In this application, we propose to use genetic, cell biological, molecular and biochemical methods in Drosophila and mouse to address the following questions: (1) When do axo-glial SJs form during embryonic development in fly; Does axo-glial SJ formation coincide with the expression of NRX, CONT and NRG? Are axo-glial SJs absent in nrx, cont and nrg mutants? (2) What is the relationship of NRX, CONT and NRG to the formation of SJs in fly? Are NRX, CONT and NRG sufficient for the formation of SJs? (3) What is the loss of function phenotype of the mouse homolog of NRG (NF155)? What role does NF155 play in the formation of paranodal axo-glial SJs? Our studies will provide new insights into the mechanisms responsible for axon-glial interactions. In the future, these studies will advance our understanding of the functional deficits that accompany demyelinating disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050356-03
Application #
7404419
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Utz, Ursula
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$258,769
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Banerjee, Swati; Riordan, Maeveen (2018) Coordinated Regulation of Axonal Microtubule Organization and Transport by Drosophila Neurexin and BMP Pathway. Sci Rep 8:17337
Saifetiarova, Julia; Liu, Xi; Taylor, Anna M et al. (2017) Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy. J Neurosci Res 95:1373-1390
Banerjee, Swati; Mino, Rosa E; Fisher, Elizabeth S et al. (2017) A versatile genetic tool to study midline glia function in the Drosophila CNS. Dev Biol 429:35-43
Banerjee, Swati; Venkatesan, Anandakrishnan; Bhat, Manzoor A (2017) Neurexin, Neuroligin and Wishful Thinking coordinate synaptic cytoarchitecture and growth at neuromuscular junctions. Mol Cell Neurosci 78:9-24
Mino, Rosa E; Rogers, Stephen L; Risinger, April L et al. (2016) Drosophila Ringmaker regulates microtubule stabilization and axonal extension during embryonic development. J Cell Sci 129:3282-94
Buttermore, Elizabeth D; Thaxton, Courtney L; Bhat, Manzoor A (2013) Organization and maintenance of molecular domains in myelinated axons. J Neurosci Res 91:603-22
Buttermore, Elizabeth D; Piochon, Claire; Wallace, Michael L et al. (2012) Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development. J Neurosci 32:4724-42
Chen, Yu-Chi; Lin, Yong Qi; Banerjee, Swati et al. (2012) Drosophila neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission. J Neurosci 32:16018-30
Thaxton, Courtney; Pillai, Anilkumar M; Pribisko, Alaine L et al. (2011) Nodes of Ranvier act as barriers to restrict invasion of flanking paranodal domains in myelinated axons. Neuron 69:244-57
Buttermore, Elizabeth D; Dupree, Jeffrey L; Cheng, JrGang et al. (2011) The cytoskeletal adaptor protein band 4.1B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons. J Neurosci 31:8013-24

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