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    Hong-Sheng Li PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentNeurobiology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
    Phone508-856-6702
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentNeuroscience

        Overview 
        Narrative

        Academic Background

         

        B.Sc. with high honors in Biochemistry,
        Wuhan University, China
        1991
        Ph.D., Shanghai Brain Research Institute,
        Chinese Academy of Science, China
        1996
        Postdoctoral Fellow, Johns Hopkins University 1996-2001
        The Albert L. Lehninger Postdoctoral Fellow Award, Johns Hopkins University 2001

        Molecular Dissection of Drosophila Vision

        We are using the Drosophila visual system as a genetic model to study molecular and cellular mechanisms underlying sensory functions.  By generating new fly mutants and characterizing visual phenotypes, we are investigating how photoreceptor neurons maintain their sensitivity to light and achieve rapid signaling, how visual signals are processed by interneurons, how visual glia support and modulate neuronal signaling, and how derailed signaling activities lead to neuronal degeneration in the eye.  Study on these topics will contribute to our understandings of sensory functions and neuron-glia interactions in general.  In addition, it will provide important insight to the pathology of retinitis pigmentosa and age-related macular degeneration, two human retinal disorders due to loss of photoreceptor neurons.

        Using a combination of genetic, biochemical, electrophysiological, and imaging approaches, in addition to behavioral assays, we are currently focusing on the following two research directions.

        Multifaceted regulation of rhodopsin in fly photoreceptors

        The Drosophila visual transduction occurs in rhabdomere, a highly packed microvillar organelle in photoreceptor neurons.  Upon light-stimulated isomerization, rhodopsin triggers a trimeric Gq protein to activate phospholipase C, which leads to the open of transient-receptor-potential (TRP) channels and the depolarization of photoreceptor.  For response to repetitive stimuli, the visual transduction needs to be terminated promptly after each stimulus, which depends on deactivation of rhodopsin as well as closing of TRP channels.  Using new fly mutants, we have demonstrated that photoreceptors employ multiple mechanisms to regulate the signaling of rhodopsin, and that these regulations are important both for the speed of visual response and for the photoreceptor sensitivity to light. 

        In addition to the classic, arrestin-mediated regulation, fly rhodopsin is deactivated through a mechanism that depends on a Ca2+/calmodulin-stimulated transcription factor dCAMTA.  We have identified several target genes of dCAMTA, and found that overexpression of an F-box gene dFbxl4 rescued the mutant phenotype of dCAMTA.  We will continue to investigate whether Rh1 undergoes dFbxl4-dependent ubiquitination, and whether the ubiquitination is important for Rh1 deactivation.  We have also obtained a knockout (KO) mouse line for CAMTA1, the mammalian homologue of dCAMTA, and observed similar visual defects in homozygous KO mice based on electroretinogram recordings.  Importantly, the level of mouse Fbxl4 was reduced in CAMTA1 KO mice.  Thus, the visual function of dCAMTA could be conserved from fly to mammals. 

        Intriguingly, prompt deactivation of rhodopsin is also important for the maintenance of photoreceptor sensitivity.  In both dCAMTA mutant flies and a mutant lacking a visual arrestin Arr2, prolonged activation of Gq by rhodopsin triggered excessive endocytosis of the major rhodopsin Rh1 during light exposure, leading to reduced photoreceptor sensitivity to light.  In addition to the Rh1 deactivation, a CUB and LDLa domain protein (CULD) antagonizes Arr1-mediated Rh1 endocytosis for the maintenance of visual sensitivity.

        As in human retinitis pigmentosa, mutations of rhodopsin and its regulatory molecules are major causes of retinal degeneration in the fly.  We have identified multiple types of retinal degeneration in fly mutants:  in older dCAMTA and arr2 mutants, excessive endocytosis of rhodopsin led to vacuolar degeneration of photoreceptor in a Ca2+-dependent manner; in a tadr (torn and diminished rhabdomeres) mutant, stimulated Gq protein failed to dissociate from the membrane and caused rhabdomere-initiated photoreceptor degeneration. These degeneration processes could also occur in human retinal disorders.

        The importance of glia to visual signal transmission 

        In the first visual neuropil region (lamina), fly photoreceptor axons release histamine upon light stimulation to hyperpolarize projective secondary sensory neurons and laminar local neurons. We recent found that a gap junction-dependent multicellular glial network mediates a long-distance recycling pathway of histamine for sustained visual transmission and normal visual alert response.  More importantly, we found that two ion channels in glia, Irk2 and GluCl, are essential for visual transmission in the lamina. We are currently investigating how glia receive neuronal signals through these channels and how these glial ion channels facilitate the visual transmission between photoreceptors and laminar neurons.



        Rotation Projects

        Rotation projects

        Rotation students in the lab will have the following choices of research projects:

        1) Further characterize the dCAMTA/dFbxl4-mediate deactivation of rhodopsin and the morphological defects due to loss of this pathway.

        2) Participate in the characterization of additional mutant flies that have defective rhodopsin regulation, and investigate why abnormal rhodopsin signaling leads to retinal degeneration.

        3) Explore the functions of rhodopsin regulatory molecules in other receptor signaling cascades.

        4) Isolate new fly mutants with impaired GPCR signaling.



        Post Docs

        A postdoctoral position is available to study in this laboratory. Contact Dr. Li for additional details.

        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Hu W, Wan D, Yu X, Cao J, Guo P, Li HS, Han J. Protein Gq modulates termination of phototransduction and prevents retinal degeneration. J Biol Chem. 2012 Apr 20; 287(17):13911-8.
          View in: PubMed
        2. Cao J, Li Y, Xia W, Reddig K, Hu W, Xie W, Li HS, Han J. A Drosophila metallophosphoesterase mediates deglycosylation of rhodopsin. EMBO J. 2011 Sep 14; 30(18):3701-13.
          View in: PubMed
        3. Venkatachalam K, Wasserman D, Wang X, Li R, Mills E, Elsaesser R, Li HS, Montell C. Dependence on a retinophilin/myosin complex for stability of PKC and INAD and termination of phototransduction. J Neurosci. 2010 Aug 25; 30(34):11337-45.
          View in: PubMed
        4. Ni L, Guo P, Reddig K, Mitra M, Li HS. Mutation of a TADR protein leads to rhodopsin and Gq-dependent retinal degeneration in Drosophila. J Neurosci. 2008 Dec 10; 28(50):13478-87.
          View in: PubMed
        5. Han J, Reddig K, Li HS. Prolonged G(q) activity triggers fly rhodopsin endocytosis and degradation, and reduces photoreceptor sensitivity. EMBO J. 2007 Dec 12; 26(24):4966-73.
          View in: PubMed
        6. Gong P, Han J, Reddig K, Li HS. A potential dimerization region of dCAMTA is critical for termination of fly visual response. J Biol Chem. 2007 Jul 20; 282(29):21253-8.
          View in: PubMed
        7. Han J, Gong P, Reddig K, Mitra M, Guo P, Li HS. The fly CAMTA transcription factor potentiates deactivation of rhodopsin, a G protein-coupled light receptor. Cell. 2006 Nov 17; 127(4):847-58.
          View in: PubMed
        8. Xu H, Lee SJ, Suzuki E, Dugan KD, Stoddard A, Li HS, Chodosh LA, Montell C. A lysosomal tetraspanin associated with retinal degeneration identified via a genome-wide screen. EMBO J. 2004 Feb 25; 23(4):811-22.
          View in: PubMed
        9. Ma HT, Venkatachalam K, Li HS, Montell C, Kurosaki T, Patterson RL, Gill DL. Assessment of the role of the inositol 1,4,5-trisphosphate receptor in the activation of transient receptor potential channels and store-operated Ca2+ entry channels. J Biol Chem. 2001 Jun 1; 276(22):18888-96.
          View in: PubMed
        10. Li HS, Montell C. TRP and the PDZ protein, INAD, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. J Cell Biol. 2000 Sep 18; 150(6):1411-22.
          View in: PubMed
        11. Li HS, Xu XZ, Montell C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron. 1999 Sep; 24(1):261-73.
          View in: PubMed
        12. Wes PD, Xu XZ, Li HS, Chien F, Doberstein SK, Montell C. Termination of phototransduction requires binding of the NINAC myosin III and the PDZ protein INAD. Nat Neurosci. 1999 May; 2(5):447-53.
          View in: PubMed
        13. Li HS, Porter JA, Montell C. Requirement for the NINAC kinase/myosin for stable termination of the visual cascade. J Neurosci. 1998 Dec 1; 18(23):9601-6.
          View in: PubMed
        14. Xu XZ, Wes PD, Chen H, Li HS, Yu M, Morgan S, Liu Y, Montell C. Retinal targets for calmodulin include proteins implicated in synaptic transmission. J Biol Chem. 1998 Nov 20; 273(47):31297-307.
          View in: PubMed
        15. Li HS, Zhao ZQ. Small sensory neurons in the rat dorsal root ganglia express functional NK-1 tachykinin receptor. Eur J Neurosci. 1998 Apr; 10(4):1292-9.
          View in: PubMed
        16. Xu XZ, Li HS, Guggino WB, Montell C. Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell. 1997 Jun 27; 89(7):1155-64.
          View in: PubMed
        17. Li HS, Zhao ZQ. [Progress in the study of the molecular neurobiology of substance P]. Sheng Li Ke Xue Jin Zhan. 1994 Jan; 25(1):37-41.
          View in: PubMed
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