Research Interests:
Cell adhesion is essential to the development of nervous system,
from neuronal migration to axon guidance and fasciculation to synapse
formation. This spectrum of cell adhesion events is typically mediated
by the same adhesion molecules.
L1CAM functions. To understand how cell adhesion molecules
function in such a wide range of events, we are 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). However,
it is not clear how loss of L1 activity results in the CRASH syndrome.
The C. elegans L1 homologue, LAD-1, is highly expressed
in the nervous system. Initial characterization of lad-1 mutants
indicates several defects in the nervous system, which include misplacement
of neuronal cell bodies and deficient synapse transmission. Determination
of the molecular nature of these defects, which is currently underway,
will help better understand the aetiology of the CRASH syndrome.
L1CAM and doublecortin. LAD-1 is linked to the spectrin-actin
cytoskeleton via the adaptor protein, ankyrin. This ankyrin binding
is negatively regulated by the Fibroblast Growth Factor Receptor
(FGFR)-activated tyrosine-phosphorylation of LAD-1. Phosphorylated
L1 has been shown to interact biochemically with the microtubule
binding protein, doublecortin. Mutations in human doublecortin result
in the X-linked lisencephaly and doublecortex syndromes, which are
thought to be caused by deficient neuronal migration. We are currently
determining how doublecortin and L1 genetically interact in the
development of the nervous system.
Selected Publications:
Wang X, Kweon J, Larson S, Chen L.A role for the C. elegans L1CAM homologue
lad-1/sax-7 in maintaining tissue attachment.Dev Biol. 2005 Aug 15;284(2):273-91.
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.
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