The central nervous system is organized into ensembles of cells that can be identified by their anatomy and physiology. That is to say, there are populations of cells with dedicated structure and function. Two fundamental questions about this organization are: what are the mechanisms by which any particular neuronal ensemble establishes its identity and second what are the mechanisms by which ensemble find each other and establish their particular connectivity? Considerable evidence has shown environmental factors to be important in regulating development. The extracellular matrix (ECM) is a rich source of such signals. Laminins are key elements of the ECM and several human diseases are known to result from genetic disruptions in laminin genes or laminin receptor genes, including ocular disease as well as congenital brain malformations. Our long-term goal is to understand the mechanism of human disease as well as develop novel therapeutics and diagnostics.
We use the vertebrate retina as a "simple" model system to study the role of the ECM in CNS development. We have shown that laminins are critical to the normal development in the retina. Using in vivo and in vitro experimental manipulations, we have shown that deletion of various laminins result in retinal dysgenesis. The abnormalities include photoreceptor dysplasia and photoreceptor synaptic disruption. We have observed dysgenesis of retinal ganglion cells and hypoplasia of the optic nerve in our mutants. We are currently investigating the molecular and signaling mechanisms that produce these phenotypes. Recently, we have turned our attention to cortical and cerebellar development. We have shown that laminin mutants have disruptions in the cortical formation. Cortical lamination is disrupted in these mice, along with radial glial organization, the principle cellular scaffold along which cortical neurons migrate and there are ectopic neurons on the surface of the brain. These malformations phenocopy some aspects of human cortical dysgenesis called cobblestone lissencephaly.
Netrins, a family of laminin related molecules, have been long thought to be involved in neuronal migration. We have shown that these molecules are expressed in the non-neural tissues and are involved in branched epithelial development. In the CNS, we have shown one molecule, netrin-4 (formerly b-netrin) is specifically involved in the regulation of the granule cell population in the cerebellum. Recent data demonstrates that neural guidance molecules (laminin and netrins) may be involved in vascular development. Netrins and laminins are important in angiogenesis. We are currently exploring the roles of these molecules in retinal vascular biology.
Our immediate goal is to identify the cell binding and cytomatrix molecules that complex with these ECM molecules. Our short-term goal is to identify the role of these molecules in human disease. Our long-term goal is to incorporate biological active molecules into polymers that can be used in neural repair strategies.
Recent Selected Publications
Egles, C., Claudepierre, T., Manglapus, M.K., Champliaud, M-F., Brunken, W.J., and Hunter, D.D. (2007) Precise Organization of CNS Synapses Requires Laminins Containing the β2 Chain. Molecular and Cellular Neurobioscience 34: 288-298.
Aisenbrey, S., Zhang, M., Bacher, D., Yee, J., Brunken, W.J., and Hunter, D.D. (2006) Retinal pigment epithelial cells synthesize laminins including laminin 5 and adhere to them using α3- and α6-containing integrins. Investigative Ophthalmology and Visual Sciences 47: 5537-5544.
W.J. Brunken Claudepierre, T., Manglapus M.K., Hunter D.D. (2006) Structure and Function of Retinal Synapses: Role of Cell Adhesion Molecules and Extracellular Matrix. In Principles and Practice of Clinical Electrophysiology of Vision, 2nd Edition; eds Heckenlively and Arden; MIT Press Cambridge, MA.
Claudepierre, T., Manglapus, M.K., Marengi, N., Radner, S., Champliaud, M-F., Tasanen, K., Bruckner-Tuderman, L., Hunter, D.D., and Brunken, W.J. (2005) Collagen XVII And BPAG1 Expression In The Retina: Evidence For An Anchoring Complex In The CNS. Journal of Comparative Neurology 487: 190-203.
Liu, Y., Stein, E., Oliver, T., Li, Y., Brunken, W.J., Koch, M., Tessier-Lavigne, M., and Hogan, B.L.M. (2004) Novel role for Netrins in regulating epithelial behavior during lung branching morphogenesis. Current Biology 14:897-905
Hunter, D.D., Zhang, M., Ferguson, J.W., Koch, M., and Brunken, W.J. (2004) The extracellular matrix component WIF-1 is expressed during, and can modulate, retinal development. Molecular and Cellular Neuroscience 27: 477-488.
Koch, M., Murrell, J., Hunter, D.D., Olsen, P., Jin, W., Brunken, W.J., and Burgeson, R.E. (2000) A Novel Member of the Netrin Family,β-netrin, Shares Homology with β Chain of Laminin: Identification, Expression and Functional Characterization. Journal of Cell Biology 151: 221-234
Libby, R. T., Champliaud, M.F., Claudepierre, T., Xu, Y., Gibbons, E.P., Koch, M., Burgeson, R.E., Hunter, D.D. and Brunken, W.J. (2000) Expression of laminins in the central nervous system: characterization and localization of two novel laminins. Journal of Neuroscience 20: 6517-6528.
Koch, M., Olsen, P., Albus, A. Jin, W., Hunter, D.D., Brunken, W.J., Burgeson, R.E. and Champliaud, M-F. (1999) Characterization and expression of the laminin γ3 chain: A novel, non-basement membrane, associated laminin chain. Journal of Cell Biology 145: 605-617.
Libby, R.T., Lavalle, C., Balkema, G.W., Brunken, W.J. and Hunter, D.D. (1999) Disruption of laminin β2 chain production causes alterations in morphology and function in the central nervous system. Journal of Neuroscience 19: 9399-9411.
List of Publications (Pub Med)
Lab Members
Postdoctoral Researchers:
Germán Pinzón-Duarte, M.D.; University of Bogotá, Colombia
german.pinzon-duarte@downstate.edu
Marjorie J Rico, M.D., Ph.D.; SUNY Downstate Medical Center
marjorie.rico@downstate.edu
Graduate Students:
Aarti Kuver, MCB Program
aarti.kuver@downstate.edu
Gopalan Gnanaguru, MCB Program
gopalan.gnanaguru@downstate.edu
Research Associates:
Zeng-Xiu Liu,
zengxiu.Liu@downstate.edu
Galina Bachay,