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Douglas
W. DeSimone
Professor of Cell Biology
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Research Interest
CELL ADHESION AND VERTEBRATE DEVELOPMENT
The research in my laboratory
is centered on understanding basic cellular mechanisms involved in patterning
morphogenetic change in the early vertebrate embryo. While the past
several years have witnessed remarkable advances in our understanding
of molecular mechanisms likely to be involved in controlling development
at the level of the gene, downstream cellular events that mediate morphogenetic
movements remain poorly understood. A central challenge, therefore,
is to identify the molecular interactions involved in "shaping" the
early embryo.
Figure 1:
Left panel is neurula stage Xenopus embryo processed by "whole mount"
in situ hybridization to detect mRNAs encoding ADAM 13. ADAM 13 mRNA
is localized in the head in "streams" of migrating neural crest cells.
The mRNA is also expressed in the somites. The right panel shows immunofluorescence
from a "triple-labelled" frozen section of a tailbud stage embryo. ADAM
13 is shown in green, fibronectin in red and nuclei are blue. The section
reveals that ADAM 13 protein is localized to the end junctions of individual
somitic cells.
Our research focuses on events
occurring at the embryonic cell surface that involve cell adhesion,
migration and signalling. At the heart of this effort is our work on
integrins, which are a large family of transmembrane receptors that
bind to components of the extracellular matrix (ECM) and to other cell
surface receptors. One of the most significant features of integrins
is that they serve as transmembrane links between ECM molecules and
the actin cytoskeleton. Integrins have been shown to participate in
both "outside-in" and "inside-out" signalling events that influence
cell adhesion, cytoskeletal organization, and gene expression. We are
utilizing a variety of immunologic, molecular and "reverse genetic"
approaches to determine the functions of integrins and ECM proteins
in development. Our primary system of study makes use of the eggs and
embryos of the amphibian, Xenopus laevis. We are testing the general
hypothesis that adhesion molecules such as integrins confer "adhesive
identities" to specific cells and tissues during development and, thus,
direct the cellular movements and interactions that are required for
embryogenesis to proceed.
Other areas of current interest
include the early development of the vascular system and mechanisms
of neural crest cell migration. In recent months we have initiated separate
studies to investigate molecular events involved in amphibian blood
vessel formation and the adhesion and migration of cranial neural crest
cells, the latter of which give rise to a number of important structures
in the head. Our neural crest studies focus on the role of a newly described
family of proteins called the ADAMs (A Disintegrin And Metalloprotease).
In collaboration with Dr. Judy White's lab we have identified a novel
member of this family that is expressed in Xenopus cranial neural crest
cells. We are now cloning the murine ortholog of this protein. Our long
term goal is to disrupt the expression of this and other ADAM genes
in mouse neural crest using homologous recombination methods in order
to elucidate their functions in vivo.
Representative Recent Publications
- Hens, M.D. and DeSimone,
D.W. 1995. Molecular analysis and developmental expression of the
focal adhesion kinase, pp125FAK in Xenopus laevis.
Dev. Biol. 170: 274-288.
- Ramos, J.W. and DeSimone,
D.W. 1996. Xenopus embryonic cell adhesion to fibronectin: Position-specific
activation of RGD and synergy-region-dependent migratory behavior
at gastrulation J. Cell Biol. 134: 227-240.
- Lallier, T.E., Whittaker,
C.A. and DeSimone, D.W. 1996. Integrin a6 is required for early nervous
system development in Xenopus laevis.
Development 122: 2539-2554.
- Ramos, J.W., Whittaker,
C.A. and DeSimone, D.W. 1996. Integrin adhesive activity is spatially
controlled by inductive signals at gastrulation.
Development 122: 2873-2883.
- Alfandari, D., Wolfsberg,
T.G., White, J.M. and DeSimone, D.W. 1997. A novel ADAM cDNA expressed
in somitic mesoderm and neural crest cells during Xenopus laevis embryonic
development. Dev. Biol. 182:314-330.
- Meng, F., Whittaker, C.A.,
Ransom, D.G. And DeSimone, D.W. 1997. Cloning and characterization
cDNAs encoding the integrin a2 and a3 subunits from Xenopus laevis.
Mech. of Dev. 67: 141-155.
- Urry, L.A., Whittaker,
C.A., Duquette, M., Lawler, J. and DeSimone, D.W. 1998. Thrombospondins
in early Xenopus embryos: dynamic patterns of expression suggest diverse
roles in nervous system, notochord and muscle development. Dev. Dynamics
211:390-407.
- Cohen, M.W., Hoffstrom,
B.G. and DeSimone, D.W. 2000. Active zones on
motor nerve terminals contain a3b1 integrin. J. Neuroscience 20:4912-4921.
- Lallier, T.E. and DeSimone,
D.W. 2000. Separation of neural induction
and neurulation in in Xenopus. Developmental Biology 225: 135-150.
- Alfandari, A., Cousin,
H., Gaultier, A., Smith, K., White, J.M., Darribere, T. and DeSimone,
D.W. 2001. Xenopus ADAM13 is a metalloprotease required for cranial
neural crest migration. Current Biology 11:918-930
- Marsden, M. and DeSimone,
D.W. 2001 Regulation of cell polarity, radial
intercalation and epiboly in Xenopus: Roles for integrin and fibronectin.
Development 128: 3635-3647.
- Davidson, L. A., Hoffstrom,
B.G., Keller, R. and DeSimone, D.W. 2002. Mesendoderm migration and
mantle closure during Xenopus laevis gastrulation: combined roles
for integrin a5b1, fibronectin and tissue geometry.
Dev. Biol. 242: 109-129.
- Smith, K.M., Gaultier,
A., Cousin, H., Alfandari, D., White, J.M. and
DeSimone, D.W. 2002. The cysteine-rich domain regulates ADAM protease
function in vivo. J. Cell Biol. 159: 893-902.
- Dzamba, B.D., Bolton,
M.A., and DeSimone, D.W. 2002. The Integrin
Family of Cell Adhesion Molecules. In Cell Adhesion: Frontiers in
Molecular Biology. Mary Beckerle, editor. Oxford University Press,
Oxford, UK pp 100-154.
For more information email
dwd3m@virginia.edu.
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