MEGAN E. WILLIAMS
Assistant Professor of Neurobiology and Anatomy
The Williams Lab Home Page
Neurobiology of Disease
Molecular mechanisms that regulate synapse formation and specificity of neural circuits
Proper function of the brain depends on precise synaptic connections that arise during development. This feature, known as synaptic specificity, requires that neurons recognize correct synaptic partners, often among many cell types, and then develop appropriate types of synapses. Synaptic defects are thought to underlie many types of mental and cognitive dysfunction, including epilepsy and autism spectrum disorders and despite the importance of specific neural connections, there is very little known about molecular mechanisms that regulate the formation of synaptic specificity in the mammalian brain.
The overall goals of my lab are to:
To accomplish these goals, we use the rodent hippocampus as a model system. The hippocampus is an important relay center for cognition and although its connectivity patterns are well understood, very little is known about how specific connections develop and what the consequences are of a mis-wired circuit on learning and memory. Surprisingly, dissociated hippocampal neurons retain many aspects of specificity and largely connect in the culture dish as they do in the brain. Cultured neurons are conducive to genetic and pharmacological manipulations and therefore, provide an unprecedented tool for investigating the molecular basis of synaptic specificity. Cultured neurons are not, however, a complete substitute for the brain. Therefore, we also use a variety of molecular and imaging techniques including transgenic mice, viruses, in utero electroporation, electron and confocal microscopy to investigate how the molecules and mechanisms that we identify in culture function in the intact brain during development, disease, and behavior.
Martin, E.A.*, Muralidhar, S.*, Wang, Z., Cervantes, D.C., Basu, R., Taylor, M.R., Hunter, J., Cutforth, T., Wilke, S.A., Ghosh, A., and Williams, M.E. (2015) The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus. eLife, 2015;4:e09395
Basu, R., Taylor, M., and Williams, M.E. (2015) The classic cadherins in synaptic specificity. Cell Adhesion and Migration, 9(3):193-201. doi: 10.1080/19336918.2014.1000072. Epub 2015 Apr 2.
Viswanathan, S., Williams, M.E., Bloss, E.B., Stasevich, T.J., Speer, C.M., Nern, A., Pfeiffer, B.D., Hooks, B.M., Li, W.P., English, B.P., Tian, T., Henry, G.L., Macklin, J.J., Patel, R., Gerfen, C.R., Zhuang, X., Wang, Y., Rubin, G.M., and Looger, L.L. (2015) High-performance probes for light and electron microscopy. Nature Methods, Jun;12(6):568-76. doi: 10.1038/nmeth.3365. Epub 2015 Apr 27.
Wilke, S.A., Hall, B.J., Antonios, J., DeNardo, L., Otto, S., Yuan, B., Chen, F., Robbins, E.M., Tiglio, K., Williams, M.E., Qiu, Z., Biederer, T., and Ghosh, A. (2012) NeuroD2 Regulates Development of Hippocampal Mossy Fiber Synapses. Neural Development, 7:9.
Williams, M.E., Wilke, S.A., Daggett, A., Davis, E., Otto, S., Ripley, B., Bushong, E.A., Ellisman, M., Klein, G., and Ghosh, A. (2011) Cadherin-9 regulates input-specific synaptic differentiation in the developing hippocampus. Neuron, 71:640-655. **featured with a Neuron Preview plus rated "must read" by F1000
Ripley B*, Otto S*, Tiglio K, Williams ME, and Ghosh A. Regulation of synaptic stability by AMPA receptor reverse signaling. 2011 PNAS 108(1):367-372. *denotes co-authorship
Williams, M.E., DeWit, J., and Ghosh, A. (2010) Molecular mechanisms of synaptic specificity in developing neural circuits. Neuron, 68(1);9-18 (Review).
Williams, M.E.*, Lu, X.*, McKenna, W.L.*, Washington, R., Boyette, A., Strickland, P., Dillon, A., Kaprielian, Z., Tessier-Lavigne, M., and Hinck, L. (2006) UNC5A promotes neuronal apoptosis during spinal cord development independent of netrin-1. Nature Neuroscience, 9(8):996-998. *denotes co-authorship
Williams, M.E.*, Wu, S.*, McKenna, W.L.*, and Hinck, L. (2003) Surface expression of the netrin receptor UNC5H1 is regulated by a PICK1/PKC dependent mechanism. J. Neuroscience, 23:11279-11288. *denotes co-authorship
Williams, M.E., Strickland, P., Watanabe, K., and Hinck, L. (2003) UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. J. Biol. Chem., 278:17483-17490.