Another area of ongoing interest is to investigate the role of EphB receptors in the progression of melanoma. Malignant melanomas are hard to treat compared to the other types of skin cancer. The incidence of malignant melanoma is increasing faster than that of any other malignancy in the United States, and therefore this disease represents a significant health threat now and in the future. Several studies have demonstrated the expression of B class Eph/ephrin molecules in different tumors and suggested a functional relationship between Eph/ephrin expression and tumor progression. Our recent results show that EphB family of receptor tyrosine kinases play an important role in the melanoma migration. We show that the ability of Eph receptors and ephrins to promote cell migration contribute to their effect on melanoma progression and metastasis.
In vitro model:
Primary cultures of hippocampal neurons provide an excellent system to study the process of dendritic spine/synapse formation in controlled conditions. Previously, we have developed an in vitro system where green fluorescent protein (GFP) or DiO fluorescence were used to monitor dendritic spine morphogenesis during time-course of culture (Ethell and Yamaguchi, 1999; Ethell et al., 2001, Henkemeyer et al., 2003). The dendritic spines are usually formed between 7 and 14 days in vitro (DIV). By 14 DIV most dendritic protrusions are spines; however, their maturation continues until 21 DIV. Dendritic spines are undergoing morphogenesis, described as a decrease in dendritic spine length and formation of mature mushroom-shaped or stubby spines. The morphological formation and maturation of dendritic spines directly correlates with synapse formation and synapse functioning. The dendritic spines are remarkably dynamic and can change shape over a timescale of seconds to minutes in cultured neurons, brain slices and the intact brain. The morphology and motility changes of dendritic spines are actin-based and influenced by developmental, environmental, hormonal and pathological factors. The spines can form, collapse and change shape rapidly in response to a diverse array of stimuli (molecular or cellular). The dynamic changes of dendritic spines have long been thought to provide a morphological basis for synaptic plasticity.
Mouse models:
1. The FMR1 KO mice on the FVB/N background (mouse model for Fragile X);
2. Different EphB single, double and triple knockout mice;
3. Conditional fak knockout mice, which have been engineered to express loxP-flanked fak alleles (Rico et al., 2004).
Molecular targets:
EphB receptors and ephrins, integrins, neuroligins and neurexins, matrix metalloproteases, proteoglycans.
Cellular interactions:
Synaptic axon-dendritic and glia-neuron interactions, neuro-immune interactions (interactions between neurons and microglia).
Methods:
Live imaging; confocal and two-photon microscopy, transfection of neurons in culture and in slices, recombinant proteins, siRNA, transgenic mice, real time PCR, gene cloning, in situ, 2D-analysis, flow cytometry, subcellular fractionation, immunofluorescence, histochemistry, etc.
Current Lab Members:
Dr. Tina Bilousova – Posdoctoral Res.
Dr. Michael Moeller – Postdoctoral Res.
Michelle Yang – Biochem Grad Student
Yang Shi – Neuroscience Grad Student
Kai-Ti Lin – Biomed Grad Student
Kyle Osborne – Neuroscience Grad Student
Michelle Ngo – CMDB Grad Student
Collaborators:
Dr. Monica Carson, PhD
Associate Professor,
Division of Biomedical Sciences, UCR
Riverside, CA 92521
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Dr. Douglas W. Ethell
Assistant Professor
Division of Biomedical Sciences, UCR
Riverside, CA 92521
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Dr. Mark Henkemeyer, PhD
Associate Professor,
Center for Developmental Biology and Kent Waldrep Foundation Center; University of Texas Southwestern Medical Center
Dallas, TX 75390-9133
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Dr. Peter W. Hickmott, PhD
Assistant Professor,
Department of Psychology, UCR
Riverside, CA 92521
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Dr. Elena Pasquale, PhD
Professor,
Developmental Neurobiology
The Burnham Institute
La Jolla CA 92037
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Dr. Louis F. Reichardt, PhD
Jack D. and DeLoris Lange Professor of Cell Physiology; Director, Herbert W. Boyer Program in Biological Sciences; Director, Neuroscience Program
Investigator, Howard Hughes Medical Institute
Department of Physiology, UCSF
San Francisco, CA 94143-2611
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Selected Publications (1999-2006):
Ethell, I.M. and Yamaguchi, Y. 1999. Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. J. Cell Biol. 144: 575-586.
Miura, R., Aspberg, A., Ethell, I.M., Hagihara, K., Schnaar, R.L., Ruoslahti, E. and Yamaguchi, Y. 1999. The proteoglycan lectin domain binds sulfated cell surface glycolipids and supports cell adhesion and neurite outgrowth. J. Biol. Chem. 274: 11431-11437.
Wang, H.-G., Pathan, N., Ethell, I.M., Krajewski, S., Yamaguchi, Y., Shibasaki, F., McKeon, F., Bobo, T., Franke, T.F. and Reed, J. 1999. Ca-Induced apoptosis through calcineurin dephosphorylation of BAD. Science 284: 339-343.
Gartner, A., Shostak, Y., Hackel, N., Ethell, I.M., and Thoenen, H. 2000. Ultrastructural identification of storage compartments and localization of activity-dependent secretion of neurotrophin 6 in hippocampal neurons. Mol. Cell. Neurosc. 15: 215-234.
Ethell, I.M., Hagihara, K., Miura, Y., Irie, F. and Yamaguchi, Y. 2000. Synbindin, a novel syndecan-2-binding protein in neuronal dendritic spines. J. Cell Biol. 151: 53-68.
Miura, R., Ethell, I.M. and Yamaguchi, Y. 2001. Carbohydrate-protein interactions between HNK-1-reactive sulfoglucuronyl glycolipids and the proteoglycan lectin domain mediate neuronal cell adhesion and neurite outgrowth. J. Neurochem. 76: 413-424.
Ethell, I.M., Irie, F., Kao, M.S., Couchman, J.R., Pasquale, E.B. and Yamaguchi, Y. 2001. EphB2/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31: 1001-1013.
Henkemeyer, M., Itkis, O.S., Ngo, M., Hickmott, P.W. and Ethell, I.M.. 2003. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol., 163(6):1313-26.
Ethell, I.M. and Pasquale, E.B. 2005. Molecular mechanisms of dendritic spine development and remodeling. Prog Neurobiol. 75(3):161-205. Epub 2005 Apr 2.
Hoogenraad, C.C., Milstein, A.D., Ethell, I.M., Henkemeyer, M. and Sheng, M. 2005. GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nat Neurosci. 8(7):906-915.
Moeller, M.L, Shi, Y., Reichardt, L.F. and Ethell, I.M. 2006. EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of FAK and RhoA activation. J Biol Chem. 281(3):1587-98. Epub 2005 Nov 18.
Shi, Y.and Ethell, I.M. 2006. Integrins Control Dendritic Spine Plasticity in Cultured Hippocampal Neurons through NMDAR/CaMKII Dependent Actin Reorganization. J. Neurosci., 26(6):1813-1822.
Hickmott, P.W. and Ethell, I.M. 2006. Dendritic plasticity in the adult neocortex. Neuroscientist. 12(1):16-28.
Bilousova, T., Rusakov, D., Ethell, D.W. and Ethell, I.M. 2006 MMP-7 Disrupts Dendritic Spines in Hippocampal Neurons through NMDA Receptor Activation. J. Neurochem., 97(1):44-56. Epub 2006 Mar 3.
Yang, N.-Y., Pasquale, E.B., Owen, L.B. and Ethell, I.M. 2006 EphB receptor tyrosine kinase promotes migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization. J Biol Chem., 281(43):32574-32586. Epub 2006 Aug 31.
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