The use of Stem Cells to Study the Development and Function of the Nervous System.
Work in the lab focuses on the mechanisms that control neural differentiation and neural circuit assembly. The vertebrate central nervous system contains thousands of different neuronal cell types each one of which exhibits a unique set of developmental behaviors, such as migration of young neurons, axon pathfinding and synapse formation. Individual neuronal types are generally represented by a small number of cells, often scattered within the nervous system, which limits the scope of methods applicable to their study. To overcome this problem, we have taken advantage of the capacity of embryonic stem (ES) cells to differentiate into specific types of nerve cells in vitro. We have developed a robust protocol for the differentiation of mouse ES cells into spinal motor neurons and interneurons. The goal of these studies is to use stem cell technologies in combination with mouse genetics to discover mechanisms and principles of cell fate specification and to define the developmental changes underlying neuronal maturation and aging. Beside basic studies we use mouse and human stem cell-derived motor neurons to model motor neuron degenerative diseases and as a tool for drug discovery.
1. Amoroso, M.W., Croft, G.F., Williams, D.J., O'Keeffe, S., Carrasco, M.A., Davis, A.R., Roybon, L., Oakley, D.H., Maniatis, T., Henderson, C.E., and Wichterle, H. (2013). Accelerated High-Yield Generation of Limb-Innervating Motor Neurons from Human Stem Cells. J Neurosci 33, 574-586.
2. Mazzoni, E.O., Mahony, S., Closser, M., Morrison, C.A., Nedelec, S., Williams, D.J., An, D., Gifford, D.K., and Wichterle, H. (2013a). Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nature neuroscience 16, 1219-1227.
3. Mazzoni, E.O., Mahony, S., Peljto, M., Patel, T., Thornton, S.R., McCuine, S., Reeder, C., Boyer, L.A., Young, R.A., Gifford, D.K., and Wichterle, H. (2013b). Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals. Nature neuroscience 16, 1191-1198.
4. Nedelec, S., Peljto, M., Shi, P., Amoroso, M.W., Kam, L.C., and Wichterle, H. (2012). Concentration-dependent requirement for local protein synthesis in motor neuron subtype-specific response to axon guidance cues. J Neurosci 32, 1496-1506.
5. Chen, J.A., Huang, Y.P., Mazzoni, E.O., Tan, G.C., Zavadil, J., and Wichterle, H. (2011). Mir-17-3p controls spinal neural progenitor patterning by regulating olig2/irx3 cross-repressive loop. Neuron 69, 721-735.
6. Peljto, M., Dasen, J.S., Mazzoni, E.O., Jessell, T.M., and Wichterle, H. (2010). Functional diversity of ESC-derived motor neuron subtypes revealed through intraspinal transplantation. Cell Stem Cell 7, 355-366.
7. Dimos, J.T., Rodolfa, K.T., Niakan, K.K., Weisenthal, L.M., Mitsumoto, H., Chung, W., Croft, G.F., Saphier, G., Leibel, R., Goland, R., Wichterle, H., Henderson, C.E., and Eggan, K. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221.
8. Wichterle, H., Lieberam, I., Porter, J.A., and Jessell, T.M. (2002). Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385-397.