Professor of Biological Sciences
PhD, 1994 University of Iowa
|Office:||340D Christopher S. Bond Life Sciences Center|
Mechanisms regulating neuronal development and physiology in vertebrates
Research descriptionDuring nervous system development in vertebrates, newborn neurons migrate extensively to precise locations where they participate in assembling circuits that control behaviors and functions essential for health and survival. Defective migration of neurons in different brain regions is associated with neuronal migration disorders that can lead to epilepsy, and cognitive and motor deficits. My lab is interested in understanding the cellular and molecular mechanisms regulating neuronal migration, and in examining the behavioral consequences of defective migration.
The migration of facial branchiomotor (FBM) neurons is an excellent model system to investigate neuronal migration mechanisms. My lab identified the first gene necessary for FBM neuron migration. We use the zebrafish and mouse models to dissect these mechanisms using genetic, biochemical and imaging approaches. While a large number of genes, including several functioning the Wnt/Planar Cell Polarity (PCP) signaling pathway, are required for FBM neuron migration, their mechanisms of action have remained largely obscure, in part because they may be independent of PCP signaling. Our recent work has provided insights into the roles of Wnt/PCP-associated transmembrane proteins Vangl2 and Celsr1 in respectively regulating the initiation and direction of migration of FBM neurons in the zebrafish and mouse hindbrain.
Understanding the role of Vangl2 in initiating FBM neuron migration in zebrafish and mice: We propose that Vangl2 functions in the floor plate cells in rhombomere 4 to localize signaling molecules necessary for initiating migration. We are testing this model through loss-of-function experiments in zebrafish and mice, as well as by modulating the localization of Vangl2 in floor plate cells.
Testing the role of candidate genes in FBM neuron migration in zebrafish: We have identified a promising set of candidate genes through expression profiling experiments. We are examining their roles in migration by generating loss-of-function alleles using the CRISPR/Cas9 method.
Understanding the role of Celsr1 in directing FBM neurons to migrate caudally: We propose that in mouse Celsr1 blocks migration into anterior rhombomeres by suppressing the response of FBM neurons to rostrally expressed Wnts. We are testing this model through hindbrain explant studies and mutant analyses.
Examining the behavioral and physiological consequences of defective migration: We propose that defective migration of FBM neurons results in improper assembly of the branchiomotor circuits regulating feeding. We have developed methods to measure food intake in zebrafish and are examining feeding efficiency in neuronal migration mutants. In collaboration with the Fetcho lab (Cornell), we will examine the effects on neuronal physiology and connectivity in migration mutants.
- Analysis of the role of integrin signaling in FBM neuron migration.
- Forward genetic screen for genes regulating neuronal development in the zebrafish hindbrain (collaboration with S. Ekker and K. Clark, Mayo Clinic).
- Establish of an in vitro (cell culture) system using rhombomere explants to study the roles of Wnt/PCP components in migration.
Glasco, D.M., Pike, W., Qu, Y., Reustle, L., Misra, K., Di Bonito, M., Studer, M., Fritzsch, B., Goffinet, A.M., Tissir, F., Chandrasekhar, A. The atypical cadherin Celsr1 functions non-cell autonomously to block rostral migration of facial branchiomotor neurons in mice (2016) Developmental Biology, 417 (1), pp. 40-49.
Roszko, I., Sepich, D.S., Jessen, J.R., Chandrasekhar, A., Solnica-Krezel, L. A dynamic intracellular distribution of Vangl2 accompanies cell polarization during zebrafish gastrulation (2015) Development (Cambridge), 142 (14), pp. 2508-2520.
Roszko, I., Sepich, D.S., Jessen, J.R., Chandrasekhar, A., Solnica-Krezel, L. (2015). A dynamic intracellular distribution of Vangl2 accompanies cell polarization during zebrafish gastrulation. Development, 142(14):2508-2520.
Pan, X., Sittaramane, V., Gurung, S. and Chandrasekhar, A. (2014) Structural and temporal requirements of Wnt/PCP protein Vangl2 function for convergence and extension movements and facial branchiomotor neuron migration in zebrafish. Mechanisms of Development, 131: 1-14.
Sittaramane, V., Pan, X., Glasco, D. M., Huang, P., Gurung, S., Bock, A., Li, S., Wang, H., Kawakami, K., Matise, M. P. and Chandrasekhar, A. (2013) The PCP protein Vangl2 regulates migration of hindbrain motor neurons by acting in floor plate cells, and independently of cilia function. Developmental Biology, 382(2):400-412.
Glasco, D. M., Sittaramane, V., Bryant, W., Fritzsch, B., Sawant, A., Paudyal, A., Stewart, M., Andre, P., Vilhais-Neto, G. C., Yang, Y., Song, M., Murdoch, J. N. and Chandrasekhar, A. (2012) The mouse Wnt/PCP protein Vangl2 is necessary for migration of facial branchiomotor neurons, and functions independently of Dishevelled. Developmental Biology, 369: 211-222.
Thoby-Brisson, M., Bouvier, J., Glasco, D. M., Stewart, M. E., Murdoch, J. M., Champagnat, J., Fortin, G. and Chandrasekhar, A. Brainstem respiratory oscillators develop independently of neuronal migration defects in the Wnt/PCP mouse mutant looptail. PLoS One, 7: e31140.
Burroughs-Garcia, J., Sittaramane, V., Chandrasekhar, A. and Waters, S. (2011) Evolutionarily conserved role for Gbx2 in anterior hindbrain development. Developmental Dynamics, 240: 828-838.
Qu, Y., Glasco, D.M., Zhou, L., Sawant, A., Ravni, A., Fritzsch, B., Damrau, C., Murdoch, J.N., Evans, S., Pfaff, S.L., Formstone, C., Goffinet, A.M., Chandrasekhar, A., Tissir, F. (2010). Atypical cadherins Celsr1-3 differentially regulate migration of facial branchiomotor neurons in mice. Journal of Neuroscience, 30(28):9392-9401.
Bingham. S., Sittaramane, V., Mapp, O., Patil, S., Prince, V., and Chandrasekhar, A. (2010) Multiple mechanisms mediate motor neuron migration in the zebrafish hindbrain. Developmental Neurobiology, 70: 87-99.