Department of Cell Biology Faculty
William J. Brunken, Ph.D.
Professor and Vice Chair for Research, Department of Ophthalmology
Professor, Department of Cell Biology
Department of Cell Biology - Box 5
Office: 718-221-5328; Fax: 718-221-5389; Lab: 718-221-5390, 91
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
- Denés, V., Witkovsky, P., Koch, M., Hunter, D.D., Pinzón-Duarte, G., and Brunken, W.J. Laminin Deficits Induce Alterations in the Development of Dopaminergic Neurons in the Mouse Retina. Visual Neuroscience 24: 549-562. 2007
- Nakamura, R.E.I., Hunter, D.D., Yi, H., Brunken W.J. and Hackam, A.S. Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina. BioMed Central Cell Biology 8: 52 2007 Designated Highly Accessed - over 5,200 views.
- Pinzón-Duarte, G., Daly, G., Yong, Li, Hunter, D.D., Koch, M. and Brunken, W.J. Genetic Deletion of Both β2 and γ3 Laminin Chains Produces Retinal Dysplasia. Investigative Ophthalmology and Visual Sciences 51: 1773-1782 2010 PMID: 19907020
- Hirrlinger, P.G., Pannicke, T., Winkler, U., Claudepierre, T., Varshney, S., Schulze, C., Reichenbach, R., Brunken, W.J., and Hirrlinger, J. Genetic deletion of laminin isoforms β2 and γ3 induces a reduction in Kir4.1 and aquaporin-4 expression and function in the retina. PLoS One. 6: e16106. 2011 PMID: 21283711
- Barak. T., Kwan, K.Y., Louvi, A., Demirbilek, V., Saygi, S., Tüysüz, B., Choi, M., Boyaci, H., Doerschner, K., Zhu, Y., Kaymakçalan, H., Yilmaz, S., Bakircioğlu, M., Çağlayan, A.O., Öztürk, A.K., Yasuno, K., Brunken, W.J., Atalar, E., Yalçinkaya, C., Dinçer, A., Bronen, R.A., Mane, S., Özçelik, T., Lifton, R.P., Šestan, N., Bilgüvar, K., Günel, M., Recessive LAMC3 mutations cause malformations of the occipital cortical development. Nature Genetics. 43:590-594. 2011 PMID: 21572413
- Saghizadeh, M., Soleymani, S., Harounian, A., Bhakta, B., Troyanovsky, S.M., Brunken, W.J., Pellegrini,G., and Ljubimov, A.V. Alterations of epithelial stem cell marker patterns in human diabetic corneas and effects of c-met gene therapy. Molecular Vision 17:2177-2190. 2011 PMID: 21866211
- Yebra, M., Diaferia, G.R., Montgomery, A.M., Kaido, T., Brunken, W.J., Koch, M., Hardiman, G., Crisa, L., and Cirulli, V. Endothelium-Derived Netrin-4 Supports Pancreatic Epithelial Cell Adhesion and Differentiation through Integrins α2β1 and α3β1. PLoS One 6:e22750. 2011 PMID: 21829502
- Li, Y.N., Radner, S., French, M.M., Pinzón-Duarte, G., Daly, G.H., Burgeson, R.E., Koch, M, and Brunken, W.J. The γ3 chain of laminin is widely expressed and contributes to basement membranes in mouse: Expression and Functional Studies. Matrix Biology 31:120-134. 2012 PMID: 22222602
- Li, Y.N., Pinzón-Duarte, G., Dattilo, M., Claudepierre, T., Koch, M., and Brunken, W.J. The Expression And Function Of Netrin-4 In Murine Ocular Tissue. Experimental Eye Research 96: 24-35 2012 PMID: 22281059
- Radner, S, Banos, C., Bachay, G., Li, Y.N., Hunter D. D., Brunken, W.J. and Yee, K.T. β2 and γ3 Laminins Are Critical Cortical Basement Membrane Components: Ablation of Lamb2 and Lamc3 Genes Disrupts Cortical Lamination and Produces Dysplasia. Developmental Neurobiology, 73: 209-229 2013 PMID: 22961762
- Gnanaguru, G., Bachay, G., Biswas, S., Pinzón-Duarte, G.A., Hunter, D.D., and Brunken, W.J., Laminins Containing the β2 and γ3 Chains Regulate Astrocyte Migration And Angiogenesis In the Retina. Development In the Press 2013
List of Publications (Pub Med)
Elizabeth Viriya, MD
Graduate Research Assistants
Lyl Tomlinson, BS Graduate Research Assistant, SUNY Stony Brook
Yong Li, Ph.D. Post-doctoral Fellow Harvard Biological Labs
Gopalan Gnanaguru, Ph.D. Post-doctoral Fellow Harvard Medical School
Michael Dattilo, M.D., Ph.D. Ophthalmology Resident Downstate
Lab: 718-221-5390, 91