Manzoor Bhat , PhD
Associate Professor

Education:

MS, University of Kashmir, India, 1986
PhD, Indian Institute of Science, Bangalore, India and Shiga University of     Medical Science, Shiga, Japan, 1987-1992
Postdoctoral Fellow, Howard Hughes Medical Institute, Baylor College of     Medicine, Houston, TX, 1994-1999

Genetic Dissection of Axon-Glial Interactions
in Drosophila and Mice

Axonal insulation is of fundamental importance for the proper propagation of action potentials. Our laboratory is 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 and blood-brain barrier (BBB) formation during Drosophila development. We have demonstrated that septate junctions between perineurial and inner glial cells play an essential role in axonal insulation and BBB formation. We identified the first molecular component of the glial-glial septate junctions, which was named Neurexin IV.

Figure 1 (click for larger image & description)

Mutations in Neurexin IV result in loss of septate junctions between glial cells and breakdown of the BBB, and eventual paralysis. Mutant embryos do not show any muscle contraction propagation waves that are critical for hatching and survival. Currently, genetic screens with enhancer detection using GFP expression are underway to identify additional molecular components at the septate junctions, and to understand the mechanisms of BBB formation and axonal insulation. We have extended our studies into 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 specialized septate-like junctions with the axonal axolemma. We recently showed that these junctions contain a Drosophila Neurexin IV related protein, Caspr/Paranodin (NCP1). The NCP1 mutant mice at 2-3 weeks of age exhibit tremors, ataxia, and paralysis. In the absence of NCP1, paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Another highly conserved septate junction protein, Contactin, which interacts with NCP1 is undetectable in the mutant paranodes, and potassium channels are displaced from the juxtaparanodal into the paranodal domains. These defects result in a severe decrease in peripheral nerve conduction velocity, and thus cause paralysis, demonstrating a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions.

Current studies are focused on investigating the genetic and molecular basis of the glial-glial septate junctions in Drosophila, and elucidation of the mechanisms by which vertebrate axons become organized into specialized domains. We are also interested in identifying the molecular complexes that are involved at the interface of axons and glial cells in both the systems, and how loss of these molecules affects conduction of nerve impulses and synaptogenesis.

Dr. Bhat joined the department on April 1, 2003. He was previously on the faculty of Mount Sinai School of Medicine.

Publications

Banerjee, S. and M. A. Bhat. (2007) Glial ensheathment of Peripheral axons in Drosophila. J Neurosci Res. 86(6):1189-1198.

Sousa, A.D. and M.A. Bhat. (2007) Cytoskeletal Transition at the Paranodes: the Achilles' Heel of Myelinated Axons. Neuron Glia Biol. 3(2):169-178.

Li, J., Ashley, J., Budnik, V. and M. A. Bhat. (2007) Crucial Role of Drosophila Neurexin in Proper Active Zone Apposition to Postsynaptic Densities, Synaptic Growth and Synaptic Transmission. Neuron 55: 741-755.

Pillai, A. M., Garcia-Fresco, G. P., Sousa, A. D., Dupree, J. L., Philpot, B. D. and M. A. Bhat. (2007) No Effect of Genetic Deletion of Contactin-Associated Protein (CASPR) on Axonal Orientation and Synaptic Plasticity. J. Neurosci. Res. 85, 2318-2331 (cover).

Banerjee, S. and M.A. Bhat. (2007) Neuron-glial interactions in blood-brain barrier formation. Annu. Rev. Neurosci. 30, 235-258.

Wu, V.M., M. Yu, R. Paik, S. Banerjee, Z. Liang, M.A. Bhat and G.J. Beitel. (2007) Drosophila Varicose, a member of a new subgroup of basolateral MAGUKs, is required for septate junction function. Development 134, 999-1009.

Einheber, S., M.A. Bhat and J.L. Salzer. (2006) Disrupted Axo-Glial Junctions Results in Accumulation of Abnormal Mitochondria at Nodes of Ranvier. Neuron Glia Biol. 2, 165-174.

Banerjee, S., Sousa, A.D. and M.A. Bhat. (2006) Organization and function of septate junctions: an evolutionary perspective. Cell Biochem. Biophys. 46, 65-77.

Banerjee S, Pillai AM, Paik R, Li J, Bhat MA (2006) Axonal Ensheathment and Septate Junction Formation in the Peripheral Nervous System of Drosophila . J Neurosci. 2006 Mar 22;26(12):3319-29.

Garcia-Fresco GP, Sousa AD, Pillai AM, Moy SS, Crawley JN, Tessarollo L, Dupree JL, Bhat MA (2006) Disruption of Axo-glial Junctions Causes Cytoskeletal Disorganization and Degeneration of Purkinje Neuron Axons. Proc Natl Acad Sci U S A.2006 Mar 28;103(13):5137-42.

Faivre-Sarrailh C, Banerjee S, Li J, Hortsch M, Laval M, Bhat MA. (2004).
Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function. Development 131(20):4931-42.

Bhat MA. (2003) Molecular organization of axo-glial junctions. Curr Opin Neurobiol. 13(5):552-9 (cover).

Izaddoost S, Nam SC, Bhat MA, Bellen HJ, Choi KW. (2002) Drosophila Crumbs is a Positional Cue in Photoreceptor Adherens Junctions and Rhabdomeres. Nature 416, 178-182

Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, St Martin M, Li J, Einheber S, Chesler M, Rosenbluth J, Salzer JL, Bellen HJ. (2001) Axon-glia Interactions and the Domain Organization of Myelinated Axons Require Neurexin IV/Caspr/Paranodin. Neuron 30:369-383 (cover).

Bhat MA, Izaddoost S, Lu Y, Cho KO, Choi KW, Bellen HJ. (1999) Discs Lost, a Novel Multi-PDZ Domain Protein, Establishes and Maintains Epithelial Polarity. Cell 96, 833-845.

Bellen HJ, Lu Y, Beckstead R, Bhat MA. (1998) Neurexin IV, Caspr, Paranodin, Novel Members of the Neurexin family: Encounters of Axons and Glia. Trends Neurosci. 10, 444-449.

Baumgartner S, Littleton JT, Broadie K, Bhat MA, Harbecke R, Lengyel JA, Chiquet-Ehrismann R, Prokop A, Bellen HJ. (1996) A Drosophila Neurexin is Required for Septate Junction and Blood-Nerve Barrier Formation and Function. Cell 87, 1059-1068.

Bhat MA, Philp AV, Glover DM, Bellen HJ. (1996) Chromatid Segregation at Anaphase Requires the barren Product, a Novel Chromosome Associated Protein that Interacts with Topoisomerase II. Cell 87, 1103-1114.