email: chi-bin dot chien at neuro dot utah dot edu

Associate Professor of Neurobiology and Anatomy The Chien Lab Developmental Neuroscience Molecular Neuroscience Cellular Neuroscience

B.A. 1981, Johns Hopkins University; Ph.D. 1991, California Institute of Technology; Postdoctoral Fellow, 1991-95, University of California San Diego; Postdoctoral Fellow, 1996-97, Max Planck Institute for Developmental Biology, Tuebingen, Germany.

Confocal projection through a day 5 wholemounted zebrafish embryo,
double-labelled with diI (red) and diO (green) in both eyes.

RESEARCH:

Imagine trying to find your way from the University to downtown Salt Lake on foot, using only short-range senses (smell, touch, and taste, eyes closed). This gives an idea of the task faced by a growing axon in the developing brain. The growing tip of the axon, the growth cone, has to navigate a long way across complex terrain in order to connect up with its target neurons. Nevertheless, axons somehow find their way with incredible precision, allowing the developing embryo to build itself a func-tioning nervous system. My lab studies the genes and cell behaviors that underlie axon guidance.

We use the developing zebrafish visual system as a model, for several reasons. The larvae develop quickly, so experiments are quick. They are transparent, so we can watch cells behaving in the living animal. Molecular and embryological perturbations are easy, so that we can test the mechanisms that control retinal axons. Finally, retinal axon guidance is specifically affected in 27 known mutants, so we can study the genes involved.

We use two main approaches: starting with mutants and starting with molecules. For mutants, the first step is to find out what gene is affected. We have cloned three mutants: astray, an axon guidance receptor; boxer, a gene required for heparan sulfate proteoglycan metabolism; and nevermind, a protein that likely acts in controlling the cytoskeleton. All three of these genes are related to genes implicated in human disease. The next step is to understand how these genes work. We have used in vivo and in vitro experiments to discover some surprising things about how Astray and its ligands work. Now that we have cloned boxer and nevermind, we are starting similar detailed analyses.

For molecules, we are mining the zebrafish genome for genes that may be important retinotectal path-finding. We first check whether they are expressed at the appropriate time and place in the visual system, and then quickly test their functions using antisense morpholino knockdown.

For all of our experiments, we watch what the axons do in vivo. We use timelapse microscopy to watch living growth cones as they navigate in vivo, and have made transgenic lines that express green fluorescent protein (GFP) specifically in retinal axons. We are now setting up new mutant screens using these transgenic lines.

Selected Publications

Suli, A., Mortimer, N., Shepherd, I., and Chien, C.-B. (2006) Netrin/DCC signaling controls contralateral dendrites of octavolateralis efferent neurons. Journal of Neuroscience, 26:13328-13337.

Wilson*, B. D., Ii*, M., Park*, K. W., Suli*, A., Sorensen, L. K., Larrieu-Lahargue, F., Urness, L. D., Suh, W., Asai, J., Kock, G. A. H., Thorne, T., Silver, M., Thomas, K. R., Chien, C.-B., Losordo, D. W., and Li, D. Y. (2006) Netrins promote developmental and therapeutic angiogenesis. Science, in press.*=equal contributions.

Fricke, C., and Chien, C.-B. (2005) Cloning of full-length zebrafish dcc and expression analysis during embryonic and early larval development. Developmental Dynamics, 234:732-739.

Lee, J. S., von der Hardt, S., Rusch, M. A., Stringer, S. E., Stickney, H. L., Talbot, W. S., Geisler, R., Nüsslein-Volhard, C., Selleck, S. B., Chien*, C.-B., and Roehl*, H. (2004) Axon sorting in the optic tract requires HSPG synthesis by ext2 (dackel) and extl3 (boxer). Neuron, 44:947-960. *=equal contributions.

Hutson, L. D., and Chien, C.-B. (2002) astray/robo2 is required for guidance and error correction in zebrafish retinal axons. Neuron, 33:205-217.

Fricke, C., Lee, J. S., Bonhoeffer, F., Geiger-Rudolph, S., and Chien, C.-B. (2001) astray, a zebrafish Roundabout required for retinal axon pathfinding. Science 292:507-510.

Reviews

Lee, J. S., and Chien, C.-B. (2004) When sugars guide axons: new insights from heparan sulphate proteoglycan mutants. Nature Reviews Genetics, 5:923-935.

Hutson, L. D., Campbell, D. S., and Chien, C.-B. (2004) Analyzing axon guidance in the zebrafish retinotectal system. Methods in Cell Biology, 76:13-35.

Chien, C.-B., and Piotrowski, T. (2002) How the lateral line gets its glia. Trends in Neurosciences, 25:544-546.

Hutson, L. D., and Chien , C.-B. (2002) Axon guidance and synaptogenesis in zebrafish. Current Opinion in Neurobiology, 12:87-92.

Collaborative papers

Barresi, M. J. F., Hutson, L. D., Chien, C.-B., and Karlstrom, R. O. (2005) Hedgehog regulated Slit expression determines commissure and glial cell position in the zebrafish forebrain. Development, 132:3643-3656.

Park, K. W., Urness, L. D., Senchuk, M. M., Colvin, C. J., Wythe, J. D., Chien, C.-B., and Li, D. Y. (2005) Identification of new Netrin family members in zebrafish: Developmental expression of netrin2 and netrin4. Developmental Dynamics, 234:726-731.

Yeo, S. Y., Miyashita, T., Fricke, C., Little, M. H., Yamada, T., Kuwada, J. Y., Huh, T. L., Chien, C.-B., and Okamoto, H. (2004) Involvement of Islet-2 in the Slit signaling for axonal branching and defasciculation of the sensory neurons in embryonic zebrafish. Mechanisms of Development, 121:315-324.

Park, K. W., Morrison, C. M., Sorensen, L. K., Jones, C. A., Rao, Y., Chien, C.-B., Wu, J. Y., Urness, L. D., and Li, D. Y. (2003) Robo4 is a vascular-specific receptor that inhibits endothelial migration. Developmental Biology, 261:251-267.

Walz, A., Anderson, R. B., Irie, A., Chien, C.-B., and Holt, C. E. (2002) Chondroitin sulfate disrupts axon pathfinding in the optic tract and alters growth cone dynamics. J. Neurobiology, 53:330-342.

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