Our work demonstrates the presence of axo-glial septate junctions (AGSJs) in Drosophila nerves and establishes structural and molecular similarities between Drosophila and vertebrate AGSJs. Drosophila proteins: Neurexin IV (NRX IV), Contactin (CONT) and Neuroglian (NRG) form a tripartite complex that localizes to AGSJs. Their murine orthologs Contactin-associated protein (Caspr), Contactin (Cont) and Neurofascin (NF155) also form a complex at the paranodal AGSJs in myelinated axons. Drosophila nrx IV, cont and nrg, and mouse Caspr, Cont and NF155 mutants all fail to organize AGSJs. In addition, double mutant combinations and triple mutants of nrx IV, cont and nrg in Drosophila show severe peripheral glial migration defects and axonal degeneration in embryonic peripheral nerves, pointing to an important relationship between axon-glial interactions and axonal/glial cytoskeleton. We also discovered that in the embryonic CNS midline NRX IV functions independent of CONT and NRG, and interacts in trans with a midline glia-specific immunoglobulin (Ig) domain protein, Wrapper (WRAP). This interaction coordinates axon-glial interactions, axonal ensheathment and glial migration in the CNS midline. Together these studies lead us to hypothesize that glial migration, ensheathment, and axon degeneration are mechanistically linked. Our findings provide the basis to approach the fundamental question of how axonal ensheathment is coordinated with underlying axonal and glial cytoskeletal elements during neuron-glial interactions. Most importantly, we ask which axon-glial signaling mechanisms are essential for maintaining axonal health and neuronal functions. Identification of these mechanisms using in vivo genetic analysis will provide a basis for our attempts to identify the cellular and molecular mechanisms precipitating pathological demyelination and impeding remyelination.

Public Health Relevance

Molecular Characterization of Axon-Glial Interactions The studies described in this renewal grant application relate to the genetic and molecular mechanisms that govern axonal ensheathment, establishment of neuro-glial scaffolds and organization of specialized electron-dense structures, the axo-glial septate junctions (AGSJs). This unique structure coordinates axonal domains and allows myelinated axons to propagate nerve impulses in a saltatory manner. Better understanding of the fundamental mechanisms that underlie axonal ensheathment and organization of axonal domains will help in designing future therapeutic strategies to myelin-related diseases or demyelination disorders like for example multiple sclerosis (MS) where remyelination is required and the axonal domain structure must be preserved to allow action potential propagation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050356-08
Application #
8411122
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2006-04-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$312,719
Indirect Cost
$101,625
Name
University of Texas Health Science Center San Antonio
Department
Physiology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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
Banerjee, Swati; Blauth, Kevin; Peters, Kimberly et al. (2010) Drosophila neurexin IV interacts with Roundabout and is required for repulsive midline axon guidance. J Neurosci 30:5653-67
Blauth, Kevin; Banerjee, Swati; Bhat, Manzoor A (2010) Axonal ensheathment and intercellular barrier formation in Drosophila. Int Rev Cell Mol Biol 283:93-128
Thaxton, Courtney; Pillai, Anilkumar M; Pribisko, Alaine L et al. (2010) In vivo deletion of immunoglobulin domains 5 and 6 in neurofascin (Nfasc) reveals domain-specific requirements in myelinated axons. J Neurosci 30:4868-76
Thaxton, Courtney; Bhat, Manzoor A (2009) Myelination and regional domain differentiation of the axon. Results Probl Cell Differ 48:1-28
Pillai, Anilkumar M; Thaxton, Courtney; Pribisko, Alaine L et al. (2009) Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J Neurosci Res 87:1773-93
Wheeler, Scott R; Banerjee, Swati; Blauth, Kevin et al. (2009) Neurexin IV and Wrapper interactions mediate Drosophila midline glial migration and axonal ensheathment. Development 136:1147-57
Banerjee, Swati; Bhat, Manzoor A (2008) Glial ensheathment of peripheral axons in Drosophila. J Neurosci Res 86:1189-98
Banerjee, Swati; Bainton, Roland J; Mayer, Nasima et al. (2008) Septate junctions are required for ommatidial integrity and blood-eye barrier function in Drosophila. Dev Biol 317:585-99

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