William Brunken, PhD

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RESEARCH ABSTRACT

The central nervous system (CNS) is organized into ensembles of cells that can be identified by their anatomy and physiology. That is, there are populations of cells with dedicated structure and function. Two fundamental questions about this organization are: (1) what are the mechanisms by which any particular neuronal ensemble establishes its identity and (2) what are the mechanisms by which ensembles find each other and establish their particular connectivity?

Considerable evidence has shown epigenetic factors to be important in regulating various aspects of 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 diseases as well as congenital brain malformations.

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. Our data demonstrate that laminins and the coupled signaling cascades regulate a wide array of developmental events in the eye. Using in vivo and in vitro experimental manipulations, we have shown that deletion of various laminins result in retinal dysgenesis. The abnormalities that are present as a result of these deletions include photoreceptor dysplasia and photoreceptor synaptic disruption. Dysgenesis of retinal ganglion cells, Müller cells and microglia are also part of the complex phenotype following deletion. In addition to disruptions in the neural organization of the retina, there are profound disruptions in retinal vascular development. Analyses of these disruptions will contribute significantly to our understanding of the pathobiology of several retinal diseases.

Confirming the utility of the retina as a model for the rest of the brain, we have shown that cortical and cerebellar development is also disrupted in laminin mutants. Cortical lamination is disrupted in laminin mutant mice, along with radial glial organization, the principle cellular scaffold along which cortical neurons migrate. In addition, there are ectopic neurons on the surface of the brain. These malformations phenocopy some aspects of human cortical dysgenesis called cobblestone lissencephaly. Indeed, mutations in one laminin gene in humans, Lamc3, have been shown to cause a very restrictive human lissencephaly.

Our studies demonstrate that laminins and laminin-related genes are critical for normal CNS development, and they implicate the involvement of laminin mutations in a host of human diseases. Our immediate goal is to identify the signaling pathways involved in these processes with the goal of understanding both normal development and the role of laminins and the molecules with which they interact in human disease. Our long-term goal is to incorporate biologically active molecules into polymers that can be used in neural repair strategies.

Recent Selected Publications

1. 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
2. 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 140: 2050-2061 2013 PMID: 23571221
3. Saghizadeh, M., Winkler, M.A., Kramerov, A.A., Hemmati, D., Ghiam, C.A., Dimitrijevich, S.D., Sareen, D., Ornelas. L., Ghiasi, H., Brunken, W.J., Maguen, E., Rabinowitz, Y.S., Svendsen, C.N., Jirsova, K., Ljubimov, A.V. A simple alkaline method for decellularizing human amniotic membrane for cell culture. PLoS One, 8(11): e79632. 2013 PMID: 24236148
4. Saghizadeh, M., Epifantseva, I., Hemmati, D.,Ghiam, C.A.,Brunken, W.J., and Ljubimov, A.V. Enhanced wound healing, kinase and stem cell marker expression in diabetic organ-cultured human corneas upon MMP-10 and cathepsin F gene silencing.Invest Ophthal Vis Sci. 54:8172-8180 2013 PMID: 24255036
5. Ramos, R.L., Siu, N.Y., Brunken, W.J., Yee, K.T., Gabel, LA., and Hoplight, B.J. Cellular and Axonal Constituents of Neocortical Molecular Layer Heterotopia. Developmental Neuroscience. 36:477-489 2014 PMID: 25247689
6. Saghizadeh, M., Dib, C.M., Brunken, W.J., and Ljubimov, A.V. Normalization of Wound Healing and Stem Cell Marker Patterns in Organ-Cultured Human Diabetic Corneas by Gene Therapy of Limbal Cells.Experimental Eye Research 129:66-73 2014 PMID: 25446319
7. Kociok, N. Crespo-Garcia, S., Liang, Y., Klein, S.V., Nürnberg, C., Reichhart, N., Skosyrski, S., Moritz, E., Maier, A., Brunken, W.J., Strauß, O., Koch, M., Joussen, A.M. Lack of netrin-4 modulates pathologic neovascularization in the eye. Scientific Reports. 6:18828. doi: 10.1038/srep18828. 2016 PMCID: PMC4702134
8. Biswas, S., Bachay, G., Chu, J., Hunter, D.D., and Brunken W.J. Laminin-dependent Interaction Between Astrocytes and Microglia: A Role in Retinal Angiogenesis. American Journal of Pathology 187:2112-2127. 2017 PMCID: PMC5808181
9. Omar, M.H., Campbell-Kerrisk, M., Xiao, X., Zhong, Q., Brunken, W.J., Miner, J.H., Greer, C.A., and Koleske, A.J. CNS neurons deposit laminin a5 to stabilize synapses. Cell Reports 21(5): 1281-1292. 2017 PMCID: PMC5776391
10. Hunter, D.D., Manglapus, M.K., Bachay, G., Claudepierre, T., Dolan, M.W., Gesuelli, K.A., and Brunken, W.J. CNS synapses are stabilized trans-synaptically by laminins and proteins that interact with laminins. J Comp Neurol. 2017 Oct 12. doi: 10.1002/cne.24338. [Epub ahead of print] PMID: 29023785