Lihsia Chen, PhD

Research Techniques:

Classical and molecular genetics, Confocal and conventional light microscopy, Molecular and biochemical assays

Research Interests:

Research description: Cell adhesion is essential to the organization of multicellular organisms. Cell adhesion must be stable and strong enough to maintain tissue integrity against forces exerted by the environment and the organism itself. Yet it has to be dynamic enough to allow cells to migrate during gastrulation and tissue morphogenesis. This spectrum of cell adhesion events is typically mediated by the same adhesion molecules. Thus to carry out such diverse, these cell adhesion molecules have to integrate extracellular cues with various intracellular signaling pathways. Impaired cell adhesion function has been shown to lead to developmental malformations, tumor formation, and cancer progression, adding to the importance of understanding how these adhesion molecules work.

L1CAM functions. As a model, the Chen laboratory is focusing on the function and regulation of the L1 family of cytoskeletally-linked cell adhesion receptors in C. elegans, using genetic, molecular and biochemical approaches. Mutations in human L1 result in a neurological disorder whose symptoms are characterized by the acronym CRASH (Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus).

The lab determined that the C. elegans L1 homologue, LAD-1, is ubiquitously expressed as early as when the two-cell embryo is developing and is localized to the plasma membrane at sites of cellular contact. LAD-1 is also highly expressed in the nervous system. We have several alleles of lad-1 and are currently characterizing their mutant phenotypes. Initial characterization indicates defects in the nervous system as well as in embryogenesis. Determination of the molecular nature of these defects, which is currently underway, will help better understand the aetiology of the CRASH syndrome.

L1CAM signal transduction. LAD-1 is linked to the spectrin-actin cytoskeleton via the adaptor protein, ankyrin. The ankyrin binding motif, SFIGOY, which is located in the LAD-1 cytoplasmic tail, is subjected to tyrosine-phosphorylation. This phosphorylation event, which is dependent on the Fibroblast Growth Factor Receptor (FGFR)-activated Ras pathway, abolishes ankyrin binding. The implication of this loss of ankyrin binding is not known and is a major focus of our studies. Using antibodies that recognize only phosphorylated LAD-1, we determined that phosphorylated LAD-1 is localized to axon-muscle and epithelial adherens junctions. The function and the localization mechanism of phosphorylated LAD-1 at these specialized junctions are currently being determined.

Selected Publications:

Zhou, S., Opperman, K., Wang, X., and Chen, L.  (2008).  unc-44 ankyrinand stn-2 g-syntrophin regulate sax-7 L1CAM function in maintaining neuronal positioning in Caenorhabditis elegans.  Genetics 180:  1429-1443.

Wang, X., Zhang, W., Cheever, T., Opperman, K., Schwarz, J. Hutter, H. Koepp D., and Chen, L. (2008).  The C. elegans L1CAM homologue, LAD-2, functions as a co-receptor in MAB-20/Sema2-mediated axon guidance.” Journal of Cell Biology 180:233-46.  This publication was selected by Faculty of 1000 Biology.  See http://www.f1000biology.com/article/id/1100072/evaluation

Xuelin Wang, Junghun Kweon, Stephanie Larson and Lihsia Chen. 2005. A role for the C. elegans L1CAM homologue lad-1/sax-7 in maintaining tissue attachment. Developmental Biology 284: 273-291.

Chen, L., Ong, B., and Bennett, V. 2001. LAD-1, the C. elegans L1CAM family homologue, has essential cell adhesion roles in the early embryo, participates in cell migration, and is a substrate for phosphotyrosine-based signaling. Journal of Cell Biology 154: 841-855

Bennett, V. and Chen, L. 2001. Ankyrins and cellular targeting of diverse membrane proteins to physiological sites. Current Opinion in Cell Biology 13:61-67.

Moorthy, S., Chen, L., and Bennett, V. 2000. C. elegans Beta-G spectrin is dispensable for establishment of epithelial polarity, but essential for muscular and neuronal function. Journal of Cell Biology 149: 915-930

Book Chapter:
Nass, R. and Chen, L.  “C. elegans models of human neurodegenerative diseases:  a powerful tool to identify molecular mechanisms and novel therapaeutic targets” in The Sourcebook of Models for Biomedical Research.  Ed. Dr. Michael Conn.  Humana Press. Beaverton, OR. 2007.

To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed search menu should say PubMed
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