During development, rapidly dividing, multipotent neural precursors produce the many different kinds of neurons and glial cells that make up the central and peripheral nervous systems. During adulthood, small numbers of slowly dividing neural stem cells also give rise to new neurons and glia. What are the mechanisms that maintain neural precursors and stem cells and direct formation of distinct neurons and glia? Can knowledge of developmental mechanisms be used to promote repair of nervous systems damaged by disease or injury? We address these questions using zebrafish as a model system for two fundamental reasons. First, zebrafish embryos are transparent and develop rapidly outside the mother. By marking specific neural cells with transgenically encoded fluorescent proteins, we can directly observe cells as they are born, migrate and differentiate within intact embryos using time-lapse confocal microscopy. Second, because we can raise many zebrafish, we can screen for mutations that disrupt neural development. This is an extremely powerful approach for identifying genes essential to neural development and modeling genetic diseases of the nervous system.
Our long-term goal is to identify genes that are targets for therapies to treat developmental, degenerative and cancerous diseases of the nervous system. To get there we will integrate our work with mouse and human stem cell culture models, which will be facilitated by the rich multidisciplinary and collaborative environment of the Anschutz Medical Campus.
Park, H.-C. and Appel, B. (2003) Delta-Notch signaling regulates oligodendrocyte specification. Development 130, 3747-3755.
Park, H-C., Shin, J. and Appel, B. (2004) Spatial and temporal regulation of ventral spinal cord precursor specification by Hedgehog signaling. Development 131, 5959-5969.
Park, H.-C., Boyce, J., Shin, J. and Appel, B. (2005) Oligodendrocyte specification in zebrafish requires Notch-regulated cyclin-dependent kinase inhibitor function. Journal of Neuroscience 25, 6836-6844.
Kirby, B., Takada, N., Latimer, A.J., Shin, J. and Appel, B. (2006) In vivo imaging shows dynamic oligodendrocyte progenitor behavior during zebrafish development. Nature Neuroscience 9, 1506-1511.
Shin, J., Poling, J., Park, H.C. and Appel, B. (2007) Notch signaling regulates neural precursor allocation and binary neuronal fate decisions in zebrafish. Development 134, 1911-1920.
Park, H.C., Roberts, R., Shin, J. and Appel, B. (2007) An olig2 reporter gene marks oligodendroycte precursors in postembryonic spinal cord of zebrafish. Developmental Dynamics 236, 3402-3407.
Kucenas, S., Takada, N., Park, H.C., Woodruff, E., Broadie, K. and Appel, B. (2008) CNS-derived glia ensheath peripheral nerves and mediate motor root development. Nature Neuroscience 11, 143-151.
McFarland, K.A., Topczewska, J.M., Weidinger, G., Dorsky, R.I. and Appel, B. (2008) Hh and Wnt signaling regulate formation of olig2+ neurons in the zebrafish cerebellum. Developmental Biology 318, 162-171.
Zannino, D.A. and Appel, B. (2009) olig2+ precursors produce abducens motor neurons and oligodendrocytes in the zebrafish hindbrain. Journal of Neuroscience 25, 2322-2333.
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