Manzoor Bhat, M.S., Ph.D.
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Genetic and Molecular Dissection of Neuron-Glial Interactions in Drosophila and Mice
Intricate molecular interactions between neurons and glial cells form the underlying basis of axonal insulation across species. Mutations in human genes that affect insulation of axons are associated with profound disturbances in normal impulse conduction and significant neurological disabilities. We are investigating the genetic and molecular basis of complex and reciprocal interactions between various types of glial cells, which play a key role in axonal insulation, blood-brain barrier formation and axon guidance during Drosophila development. Our lab identified Neurexin IV, Contactin and Neuroglian as key molecular components of the glial- and axo-glial septate junctions and showed that these proteins are crucial for the organization and function of the septate junctions. Recent studies in our lab have uncovered additional molecular components which link the midline glial scaffold with midline neurons to bring about commissural axon insulation and proper midline axon guidance.
We have extended these Drosophila studies to vertebrates, where axonal insulation is achieved by myelination carried out by glial cells (Schwann cells and oligodendrocytes). The myelinated nerve fibers are organized into distinct domains that are necessary for rapid saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where myelin loops closely appose and form axo-glial septate junctions. We identified the vertebrate homologs of the Drosophila septate junction proteins and demonstrated a conserved role for these proteins in the organization and function of the axo-glial septate junctions in myelinated axons. We generated Caspr, and Neurofascin (homologs of Drosophila nrx IV and nrg, respectively) mutant mice and demonstrated that in these mutants, paranodal axo-glial septate junctions fail to form and the axonal domain organization is disrupted. These defects result in severe motor deficits, decrease in nerve conduction velocity and axonal degeneration, thus demonstrating a critical role for these proteins in axon-glial interactions in myelinated axons. Our recent studies in mice, using neuron- and myelinating glia-specific inducible-Cre lines, show that axo-glial junction disruption in adults results in slow but progressive neurological disabilities leading to paralysis. These adult mouse mutants serve as models for human myelin-related pathologies.
We are using genetic and biochemical methods to identify and characterize additional molecular complexes that are involved at the interface of axons and glial cells in Drosophila and mice, and how loss of these molecules affects conduction of nerve impulses and synaptogenesis.
Anna Taylor, Ph.D.
Saifetiarova, J., Liu, X., Taylor, A.M., Li, J. and Bhat, M.A. (2017). Axonal Domain Disorganization in Caspr1 and Caspr2 Mutant Myelinated Axons Affects Neuromuscular Junction Integrity Leading to Muscle Atrophy (in press)
Saifetiarova, J., Taylor, A.M., and Bhat, M.A. (2017) Early and Late Loss of the Cytoskeletal Scaffolding Protein, Ankyrin G Reveals its Role in Maturation and Maintenance of Nodes of Ranvier in Myelinated Axons. J Neurosci. 2661-16.2017
Taylor, A.M., Saifetyarova, J., and Bhat, M.A. (2017) Postnatal Loss of Neurofascin 186 and Neurofascin 155 Differentially Affects the Maintenance of Nodes of Ranvier and Health of Myelinated Axons. Front. Cell. Neurosci. 11:11. doi: 10.3389/fncel.2017.00011
Banerjee, S., Venkatesan, A. and Bhat, M.A. (2016) Neurexin, Neuroligin and Wishful Thinking Coordinate Synaptic Cytoarchitecture and Growth at Neuromuscular Junctions. Mol. Cell. Neurosci. 78, 9-24. (Featured on the Cover).
Mino, R.E., Rogers, S.L., Risinger, A.L., Rohena, C., Banerjee, S. and Bhat, M.A. (2016). Drosophila Ringmaker Regulates Microtubule Stabilization and Axonal Extension During Embryonic Development. J. Cell Sci. 129, 3282-3294.
Calvo, M., Richards, N., Schmid, A.B., Barroso, A., Zhu, L., Ivulic, D., Zhu, N., Anwandter, P., Bhat, M.A., Court, F.A., McMahon, S.B. and Bennett, D.L. (2016). Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury. Elife 5. pii: e12661.
Banerjee, S., Riordan, M. and Bhat, M.A. (2014). Genetic Aspects of Autism Spectrum Disorders: Insights from Animal Models. Frontiers in Cellular Neuroscience 8:58.
Schmid, A.B., Bland, J., Bhat, M. A., and Bennett, D.L.H. (2014). The relationship of nerve fibre pathology to sensory function in entrapment neuropathy. Brain. 2014 Oct 27. pii: awu288.
Green, J. A., Yang, J., Grati, M., Kachar, B. and Bhat, M.A. (2013). Whirlin, a cytoskeletal scaffolding protein, stabilizes the paranodal region and axonal cytoskeleton in myelinated axons. BMC Neuroscience 2013, 14:96
Buttermore, E.D., Thaxton, C. and Bhat, M.A. (2013). Organization and Maintenance of Molecular Domains in Myelinated Axons. J. Neurosci. Res. doi: 10.1002/jnr.23197)
Chen, Y.-C., Lin, Y.Q., Banerjee, S., Venken, K., Li, J., Ismat, A., Chen, K., Duraine, L., Bellen, H.J. and Bhat, M.A. (2012). Drosophila Neuroligin 2 is Required Presynaptically and Postsynaptically for proper Synaptic Differentiation and Synaptic Transmission. J. Neurosci. 32: 16018-16030.
Buttermore, E.D., Piochon, C., Wallace, M., Philpot, B., Hansel, C., and Bhat, M.A. (2012). Pinceau organization in the cerebellum requires distinct functions of Neurofascin in Purkinje and basket neurons during postnatal development. J. Neurosci. 32, 4724-4742.
Grati, M., Shin, J.B., Weston, M. D., Green, J., Bhat, M. A., Gillespie, P.G., and Kachar, B. (2012). Localization of PDZD7 to the Stereocilia Ankle-Link Associates this Scaffolding Protein with the Usher Syndrome Protein Network. J. Neurosci. 32: 14288-14293.
Buttermore, E.D., Dupree, J.L., Tessarollo, L. and Bhat, M.A. (2011). The Cytoskeletal Adaptor Protein Band 4.1B Is Required for the Maintenance of Paranodal Axoglial Septate Junctions in Myelinated Axons. J. Neurosci. 31, 8013-8024.