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Investigator

Chi-Hon Lee, M.D., Ph.D.

NICHD
Building 18T Room #106
18 Library Drive MSC 5431
Bethesda MD 20892-5431
Office: (301) 435-1940

Fax: (301) 496-4491
leechih@mail.nih.gov

Dr. Lee received his M.D. degree from China Medical College, Taiwan and his Ph.D. degree in Biophysics from the Rockefeller University, where he studied signal transduction by tyrosine kinases. During his postdoctoral training as a Life Sciences Research Foundation fellow at UCLA, he developed a genetic technique to study neuronal connectivity at single cell resolution. In 2002, he joined NICHD as an Investigator in the laboratory of Gene Regulation and Development. His group combines behavioral, imaging, and molecular genetic approaches to study visual circuit development and function in Drosophilia. He received NIH director's award 2008.



We interested in two key questions in neurobiology: how do genetic programs direct the formation of precise neuronal connections during development and how do the resulting neural circuits guide animal behaviors. We use the Drosophila visual system as a model because this relatively simple system shares many characteristics with vertebrate brains. For visual system development, we have been focusing on the molecular mechanisms that regulate the formation of layer- and column-specific connections made by photoreceptor axons. Our previous studies show that the adhesion molecule N-cadherin and the receptor tyrosine phosphatase LAR are required for the targeting of R7 axons to appropriate brain layers. We recently uncovered that Activin/TGF-beta signaling is required for the formation of precise retinotopic maps. Disrupting components of Activin signaling pathway results in R7 axons invading neighboring columns without affecting layer-specific targeting (figure 1). The restriction of R7 growth cones to single columns is further reinforced by repulsive interactions mediated by protocadherin Flamingo. For neural circuit function, we focus on the neuronal mechanism of color vision. We recently identified the first-order interneurons that receive direct synaptic inputs from photoreceptor neurons. These include three types of projection neurons, which likely function as color-opponent neurons, as well as one type of amacrine neurons. Using a series of genetic methods, we inactivated or restored the function of specific neuron subtypes and determined the behavioral consequences. We found that the amacrine neurons that pool multiple R7 inputs to projection neurons are required for animal's phototactic responses to ultraviolete light in preference to green light. By correlating the connectivity and functions of the first-order interneurons, we are now generating anatomical and functional maps for the visual circuits.



What happens at the R7 Target Selection?




N-cadherin and Importin-3 mutant R7 axons exhibit layer- and columnar-specific targeting defects, respectively


Figure 1. N-cadherin and Importin-3 mutant R7 axons exhibit layer- and columnar-specific targeting defects, respectively. Single R7s were rendered homozygous of wild-type (upper left panel), Ncad (upper middle), or importin-α3 (lower left and middle) mutant. The lower middle panel is an orthogonal view of the lower left panel. A schematic diagram summaries the phenotypes (right panel).

Staff Image
  • Songling Huang
    Postdoctoral Fellow
    (301) 496-3399

  • Moyi Li
    Technician
    (301) 496-3399

  • Chun-Yuan Ting
    Postdoctoral Fellow
    (301) 496-3399

  • Meiluen Yang

    (301) 496-3399

  • 1) Ting C.-Y., Lee C.-H. (2007)
  • Visual circuit development.
  • Curr Opin Neurobiol., 17, 65-72
  • 2) Yonekura S., Lei Xu, Ting C.-Y., Lee C.-H. (2007)
  • Adhesive but not signaling activity of Drosophila N-cadherin is essential for photoreceptor target selection.
  • Dev. Biol., 304, 759-70
  • 3) Ting, C.-Y., Herman, T., Yonekura S., Gao, S., Wang, J., Serpe, M., O'Connor, M.B., Zipursky, S.L., Lee, C.-H. (2007)
  • Tiling of R7 axons in the Drosophila visual system is mediated both by transduction of an Activin signal to the nucleus and by mutual repulsion.
  • Neuron, 56, 793-806
  • 4) Rister, J., Pauls, D., Schnell, B., Ting, C.-Y., Lee, C.-H., Sinakevitch, I., Morante, J., Strausfeld, N.J., Ito, K., Heisenberg, M. (2007)
  • Dissection of the Peripheral Motion Channel in the Visual System of Drosophila melanogaster.
  • Neuron , 56, 155-70
  • 5) Yonekura S., Ting C.-Y., Neves G., Hung K., Hsu S., Chiba A., Chess A., Lee C.-H. (2006)
  • The variable transmembrane domain of Drosophila N-cadherin regulates adhesive activity.
  • Mol Cell Biol., 20, 6598-6608
  • 6) Ting C.-Y., Yonekura S., Chung, P., Hsu, S., Robertson, H.M., Chiba, A., Lee, C.-H. (2005)
  • The protocadherin Flamingo is required for axon target selection in the Drosophila visual system.
  • Nat Neurosci., 6, 557-63
  • 7) Ting C.-Y., Yonekura S., Chung, P., Hsu, S., Robertson, H.M., Chiba, A., Lee, C.-H. (2005)
  • Drosophila N-cadherin functions in the first stage of the two-stage layer-selection process of R7 photoreceptor afferents.
  • Development , 132, 953-963
  • 8) Lee R. C., Clandinin T. R., Lee C.-H., Chen P.L., Meinertzhagen I. A., Zipursky S. L. (2003)
  • The protocadherin Flamingo is required for axon target selection in the Drosophila visual system
  • Nat Neurosci., 6, 557-63
  • 9) Lee, C.-H., Herman, T., Clandinin, T.R., Lee, R., Zipursky, S.L. (2001)
  • N-cadherin regulates target specificity in the Drosophila visual system.
  • Neuron, 30, 437-50
  • 10) Clandinin, T. R., Lee, C.-H.*, Herman, T., Lee, R. C., Yang, A. Y., Ovasapyan, S., and Zipursky, S. L. (2001)
  • Drosophila LAR regulates R1-R6 and R7 target specificity in the visual system
  • Neuron, 32, 237-248
  • 11) Garrity, P.A., Lee, C.-H.*, Salecker, I., Robertson, H.C., Desai, C.J., Zinn, K. and Zipursky, S.L. (1999)
  • Retinal axon target selection in Drosophila is regulated by a receptor protein tyrosine phosphatase
  • Neuron, 22, 707-717
  • 12) Lee, C.-H., Cowburn, D., Kuriyan, J. (1998)
  • Peptide recognition mechanisms of eukaryotic signaling modules
  • Methods Mol. Biol., 84, 3-31
  • 13) Zhang, Z., Lee, C.-H.*, Mandiyan, V., Borg, J.P., Margolis, B., Schlessinger, J., Kuriyan, J. (1997)
  • Sequence-specific recognition of the internalization motif of the Alzheimer's amyloid precursor protein by the X11 PTB domain
  • EMBO J., 16, 6141-6150
  • 14) Moarefi, I., LaFeyre-Bernt., M., Sicheri, F., Huse, M., Lee, C.-H., Kuriyan, J., Miller, W.T. (1997)
  • Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement
  • Nature, 385, 650-653
  • 15) Lee, C.-H., Saksela, K., Mirza, U., Chait, B. and Kuriyan, J. (1996)
  • Crystal structure of the conserved core of HIV-1 Nef complexed with a Src-family SH3 domain
  • Cell, 85, 931-942
  • 16) Lee, C.-H., Leung, B., Lemmon, M.A., Zheng, J., Cowburn, D., Kuriyan, J. and Saksela, K. (1995)
  • A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein.
  • EMBO J. , 14, 5006-5015
  • 17) Lee, C.-H., Kominos, D., Jacques, S., Margolis, B., Schlessinger, J., Shoelson, S.E. and Kuriyan, J. (1994)
  • Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase
  • Structure , 15, 423-438
  • 18) Lee, C.-H., Lee, E.-C., Tai, S.-T., Kung, H.-J., Liu, Y.-C. and Hwang, J. (1993)
  • A recombinant protein composed of Epidermal growth factor and Pseudomonas Exotoxin A with a deletion of toxin binding domain specifically kills EGF-receptor bearing cells
  • Protein Engineering, 6, 433-440
  • 19) Skolnik, E.Y., Batzer, A.G., Li, N., Lee, C.-H., Lowenstein, E., Mohammedi, M., Margolis, B. and Schlessinger, J. (1993)
  • The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
  • Science, 260, 1953-1955
  • 20) Lee, C.-H., Li, W., Nishimura, R., Zhou, M., Batzer, A.G., Myers, M.G., White, M.F., Jr., Schlessinger, J. and Skolnik, E.Y. (1993)
  • Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells
  • Proc. Natl. Acad. Sci. USA, 90, 11713-11717
  • 21) Skolnik, E.Y., Lee, C.-H., Batzer, A.G., Zhou, M., Daly, R., Backer, J., White, M.F., Jr., and Schlessinger, J. (1993)
  • The SH2/SH3 domain containing protein GRB2 implicated in RAS signaling interacts with two insulin induced substrates
  • EMBO J. , 12, 1929-1936
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