Careers | Contact Us | Directions | Trustee

La Jolla, CA ~ Orlando, FL ~ Santa Barbara, CA

About Research & Faculty Training & Education News & Events License Our Technology How to Help

RESEARCH FOCUS, BIOGRAPHY, PUBLICATIONS

Research Focus

Dr. Yamaguchi investigates synapses - highly sophisticated structures connecting nerve cells. Nerve cells communicate each other through synapses. Transmission of signals through synapses is the basis for all brain functions, including sensory recognition, motor function, and learning and memory. Dr. Yamaguchi focuses on the mechanisms of how synapses are formed. His laboratory has recently found that two cell surface proteins, called Eph receptor and syndecan-2, interact with each other and thereby send a signal toward the inside of nerve cells to induce mature synapses. Abnormalities in synapses are known to be associated with neurodevelopmental disorders such as mental retardation. Dr. Yamaguchi's findings hold promise for development of treatments for these disorders.

Biography

Yu Yamaguchi earned his M.D. from Tohoku University in Japan in 1981, followed by a Ph.D. in 1985, and training in obstetrics and gynecology at the same institute. Dr. Yamaguchi came to the Burnham Institute for Medical Research for his postdoctoral training. He was appointed to the staff in 1991.

Selected Publications

Ethell, I.M., and Yamaguchi, Y. (1999) Cell surface heparan sulfate proteoglycan syndecan-2 induces maturation of dendritic spines in rat hippocampal neurons. J. Cell Biol. 144, 575-586.2

Ethell, I.M., Irie, F., Kalo, M.S., Couchman, J.R., Pasquale, E.B., and Yamaguchi, Y. (2001) EphB2/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001-1013.3

Irie, F., and Yamaguchi, Y. (2002) EphB receptors regulate dendritic spine development via intersectin GEF, Cdc42, and N-WASP. Nature Neurosci. 5, 1117-1118.

Irie, F., Okuno, M., Pasquale, E.B., and Yamaguchi, Y. (2005) Ephrin-B-EphB signaling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nature Cell Biol. 7, 501-509.

Inatani, M., Irie, F., Plump, A.S., Tessier-Lavigne, M. and Yamaguchi, Y. (2003) Mammalian brain morphogenesis and midline axon guidance require heparan sulfate. Science 302, 1144-1146.


List of Publications via PubMed
(NIH National Library of Medicine)

 

Research Report

PROTEOGLYCANS IN THE DEVELOPING NERVOUS SYSTEM

Proteoglycans are a family of glycoproteins that carry sulfated polysaccharides (glycosaminoglycans). There are four classes of glycosaminoglycans, namely heparan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronan. Proteoglycans have been implicated in various biological processes, such as the modulation of growth factor/morphogen signaling during development and tissue remodeling, regulation of cell proliferation, adhesion, and migration. Our laboratory has been studying the role of proteoglycans in neural development and physiology.

EphB2/syndecan-2 signaling in dendritic spine development

Dendritic spines are small protrusions on the surface of dendrites that receive the vast majority of excitatory synapses. These specialized postsynaptic structures have been proposed as the primary sites of synaptic plasticity. We showed that the cell surface heparan sulfate proteoglycan (HSPG) syndecan-2 is highly concentrated in dendritic spines of mature hippocampal neurons in culture. More importantly, forced expression of syndecan-2 induces the formation of dendritic spines. This function of syndecan-2 requires its cytoplasmic domain, which contains a binding site for several PDZ domain proteins (1).

In a subsequent study, we demonstrated that syndecan-2 is phosphorylated on two tyrosine residues by EphB2, a receptor tyrosine kinase that is also concentrated in dendritic spines. Syndecan-2 and EphB2 associate to form a complex in neurons and in the brain. Phosphorylation by EphB2 is necessary for syndecan-2 to associate with EphB2 and to induce dendritic spine formation in cultured neurons. Importantly, we demonstrated in this study that hippocampal neurons transfected by dominant negative EphB2 construct could not form dendritic spines. This is the first demonstration that EphB receptor signaling plays a functional role in dendritic spine development, a key finding that has since been confirmed by several other laboratories (2). [This paper was featured as an Editor’s Choice in the October 19, 2001 issue of Science.]

EphB downstream signaling leading to dendritic spine formation

In this work, we identified a signaling pathway downstream of EphB receptors that leads to dendritic spine formation. We found that ephrinB treatment of hippocampal neurons induces Cdc42 activation temporarily coinciding with EphB2 activation. Moreover, the neuronal guanine nucleotide exchange factor intersectin binds to the cytoplasmic domain of EphB2 and is activated by a cooperative effect of EphB2 and N-WASP. Dominant negative forms of these molecules all inhibit spine formation. Thus during spine formation, EphB receptors and Arp2/3-mediated actin polymerization are functionally linked by intersectin, Cdc42, and N-WASP (3). [This paper was featured in News & Views in the same issue of Nature Neurosci.]

Regulation of AMPA receptor trafficking by EphB signaling

To gain a more comprehensive view of EphB signaling in neurons, we have performed proteomic analysis of EphB2 phosphorylation targets. This analysis revealed that synaptojanin 1, one of the key accessory molecules of clathrin-mediated endocytosis, is a substrate for EphB2. Although primarily known as a presynaptic protein, synaptojanin 1 is also present in postsynaptic sites. EphB2-dependent tyrosine phosphorylation occurs in the proline-rich domain of synaptojanin 1, which serves as binding sites for two other endocytic proteins, endophilin and amphiphysin. We also showed that perturbation of EphB receptor activity inhibits ligand-dependent AMPA receptor endocytosis (4). These observations suggest a possibility that ephrin-B/EphB signaling modulates synaptic plasticity via modulation of AMPA receptor trafficking. [This paper was featured as This Week's Featured Article in AfCS/Nature Signaling Gateway. May 2005.]

Analysis of the role of heparan sulfate in development using a conditional knockout system

To understand the role of heparan sulfate in mammalian nervous system, we created loxP-modified Ext1 allele by homologous recombination. Ext1 encodes an enzyme essential for heparan sulfate synthesis. As the first conditional knockout study using this system, we performed a developing brain-targeted Ext1 knockout using the nestin-Cre driver transgene. All the nestinCre-Ext1 conditional knockout mice died at birth, presumably due to respiratory failure. The brain of conditional knockout mice exhibited various patterning defects that are composites of those caused by mutations of multiple heparan sulfate-binding morphogens. Furthermore, these brains displayed severe guidance errors in major commissural tracts, revealing a pivotal role of heparan sulfate in midline axon guidance (5). [This paper was featured in Signal Transduction Knowledge Environment (STKE): Sci. STKE, November 11, 2003.]