Manzoor Bhat, MS, Ph.D

Research

Please Visit our website for more information: www.bhatlab.org

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.

Lab Members

Qian Shi, Ph.D. Assistant Professor/Research

Jie Li Research Assistant – Senior

Carson Zabel Research Assistant – Senior

Lacey Sell Graduate Student

Max Zern Medical Student

Alison McClellan Visiting/Summer Student

Publications

Chen, S., Venkatesan, A., Lin, W., Xie, J., Neely, G., Banerjee, S. and Bhat, M.A. (2022). Drosophila Homolog of the Human Carpenter Syndrome Linked Gene, Megf8, is Required for Synapse Development and Function. J. Neurosci. (in press)

Shi, Q., Chang, C., Saliba, A. Bhat, M.A. (2022). Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer’s Disease Model. J. Neurosci. DOI: https://doi.org/10.1523/ JNEUROSCI.2427-21.2022 (Cover Feature)

Hiramoto T, Sumiyoshi A, Yamauchi T, Tanigaki K, Shi Q, Kang G, Ryoke R, Nonaka H, Enomoto S, Izumi T, Bhat MA, Kawashima R, Hiroi N. (2021). Tbx1, a gene encoded in 22q11.2 copy number variant, is a link between alterations in fimbria myelination and cognitive speed in mice. Mol Psychiatry. 27(2):929-938.

Kunisawa, K., Hatanaka, N., Shimizu, T.; Kobayashi, K., Osanai, Y., Mouri, A., Shi, Q., Bhat, M.A., Nambu, A., Ikenaka, K. (2020). Focal loss of the paranodal domain protein Neurofascin155 in the internal capsule impairs cortically induced muscle activity in vivo. Mol. Brain 13(1):159.

Ye, Y., Orynbayev, M. Zhu, X., Lim, E. Dereddi, R., Agarwal, A., Bergles, D.E. Bhat, M.A., Paukert, M. (2020). Ethanol abolishes vigilance-dependent astrocyte network activation by inhibiting norepinephrine release. Nat. Comm. 11(1):6157.

Shi Q, Lee DY, Féliers D, Abboud HE, Bhat MA, Gorin Y (2020). Interplay between RNA-Binding Protein HuR and Nox4 As a Novel Therapeutic Target in Diabetic Kidney Disease. Mol. Metab. 36:100968.

Saifetiarova, J., and Bhat, M.A. (2019). Ablation of Cytoskeletal Scaffolding Proteins, Band 4.1B and Whirlin, Leads to Cerebellar Purkinje Axon Pathology and Motor Dysfunction. J. Neurosci. Res. 97(3), 313-331 (Journal Cover Feature).

Kunisawa K, Shimizu T, Kushima I, Aleksic B, Mori D, Osanai Y, Kobayashi K, Taylor AM, Bhat MA, Hayashi A, Baba H, Ozaki N, Ikenaka K. (2018). Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability. J Neurochem. 147(3), 395-408.

Shi Q, Saifetiarova J, Taylor AM, Bhat MA (2018) mTORC1 Activation by Loss of Tsc1 in Myelinating Glia Causes Downregulation of Quaking and Neurofascin 155 Leading to Paranodal Domain Disorganization. Front. Cell. Neurosci. 12, 201.

Taylor AM, Shi Q, Bhat MA (2018) Simultaneous Ablation of Neuronal Neurofascin and Ankyrin G in Young and Adult Mice Reveals Age-Dependent Increase in Nodal Stability in Myelinated Axons and Differential Effects on the Lifespan. eNeuro 0138-18.

Saifetiarova J, Shi Q, Paukert M, Komada M, Bhat MA (2018) Reorganization of Destabilized Nodes of Ranvier in βIV Spectrin Mutants Uncovers Critical Timelines for Nodal Restoration and Prevention of Motor Paresis. J. Neurosci.  38(28):6267-6282 (reviewed independently for the Journal Club section of the Journal)

Q. Shi, S. Viswanadhapalli, W. E. Friedrichs, C. Velagapudi, C. Szyndralewiez, S. Bansal, M.A. Bhat, G.G. Choudhury, and H. E. Abboud. (2018). Nox4 is a Target for Tuberin Deficiency Syndrome. Sci. Rep. 8, 3781.

Barron, T., Saifetiarova, J., Bhat, M.A. and Kim, J.H. (2018) Myelination of Purkinje axons is critical for resilient synaptic transmission in the deep cerebellar nucleus. Sci. Rep. 8, 1022-1033.

Banerjee S, Mino RE, Fisher ES, Bhat MA. (2017). A Versatile Genetic Tool to Study Midline Glia Function in the Drosophila CNS.  Dev. Biol. 429, 35-43.

Saifetiarova J, Liu X, Taylor AM, Li J, Bhat MA. (2017). Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy. J Neurosci Res. 95(7):1373-1390. (Journal Cover Feature).

Taylor, A.M., Saifetiarova, J., and Bhat, M.A. (2017) Postnatal Loss of Neuronal and Glial Neurofascins Differentially Affects Node of Ranvier Maintenance and Myelinated Axon Function. Front. Cell. Neurosci. 11:11. doi:

Saifetiarova J, Taylor AM, Bhat MA. (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. 37(10):2524-2538. (Journal Cover Feature) (reviewed independently for the Journal Club section of the Journal)

Banerjee S, Venkatesan A, Bhat MA. (2017). Neurexin, Neuroligin and Wishful Thinking coordinate synaptic cytoarchitecture and growth at neuromuscular junctions. Mol Cell Neurosci. 78:9-24. (Journal Cover Feature).

Mino RE, Rogers SL, Risinger AL, Rohena C, Banerjee S, Bhat MA. (2017). Drosophila Ringmaker regulates microtubule stabilization and axonal extension during embryonic development. J Cell Sci. 129 (17):3282-94.