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Projects
Heparan sulfate proteoglycans play essential
roles in the biological function of complex tissues. In
particular, mutations in the biosynthesis of these structurally
heterogeneous glycoproteins are associated with developmental
defects attributable to alterations in the normal function of
specific growth factors and morphogens. To elucidate the molecular
mechanisms of these functions we have generated mice bearing a
loss of function mutation of one heparan sulfate proteoglycan,
glypican-3, and have studied the biology of the resulting
developmental abnormalities in these animals. Our studies have
discovered defects in skeletal patterning resulting from
alterations in bone morphogenetic protein (BMP) signaling
(Paine-Saunders et al., Dev Biol 2000), which has lead further to
the identification of a novel role for heparan sulfate in
modulating the cellular localization of the BMP antagonist Noggin
(Paine-Saunders et al., J Biol Chem 2002; Viviano et al., J Biol
Chem 2004). More recent studies have uncovered a delay in
endochondral ossification associated with the loss of glypican-3
function (Viviano et al., Dev Biol 2005). This has proven to be
the result of a defect in the differentiation of osteoclasts from
hematopoietic precursors, and has lead to a new area of
investigation into this previously unappreciated role for heparan
sulfate in hematopoietic development.
The post-translational modification of core
proteins with heparan sulfate in the Golgi is the result of
complex biosynthetic machinery, involving multiple distinct
isoenzymes, which act sequentially to modify the nascent
carbohydrate chain. The resulting heparan sulfate chains are
highly heterogeneous with more than a million potential distinct
structural units represented within an eight-sugar sequence of
carbohydrate chain. Which, and whether all, of these potential
structures are synthesized in vivo is not presently known. What is
known, however, is that the structure of heparan sulfate chains is
highly regulated in a tissue-specific manner in vivo, and that
differentially expressed structures between tissues impart unique
functional binding activities to heparan sulfate in those tissues.
How this tissue-specific pattern of heparan sulfate biosynthesis
is regulated is an unknown but important element towards
understanding the biology of heparan sulfate proteoglycans. We
have initiated studies using zebrafish as a model organism to
understand the molecular genetics of the regulation of heparan
sulfate biosynthesis in vivo.
Simpson Golabi Behmel Syndrome (SGBS) is a
complex congenital overgrowth syndrome with features that include
macroglossia, macrosomia, renal and skeletal abnormalities as well
as an increased risk of embryonal cancers (Saunders et al.
Glypican-3: Simpson-Golabi-Behmel syndrome :In Molecular Basis of
Inborn Errors of Development, Oxford University Press, New York,
2004). Most cases of SGBS appear to arise as a result of either
deletions or point mutations within the glypican-3 (GPC3) gene at
Xq26, one member of a multigene family encoding for at least six
distinct glycosylphophatidylinositol-linked cell surface heparan
sulfate proteoglycans. As discussed above, molecular genetic
approaches in model organisms are leading to important discoveries
about the functions of these molecules in growth factor signaling,
which in-turn are providing important insights into the molecular
basis of SGBS in humans. Despite these advances, there remains a
paucity of information about the natural history of SGBS, optimal
medical management strategies, and whether select mutations
influence the SGBS phenotype and risk of cancer. To this end an
International SGBS Registry (http://peds.wus
tl.edu/hemonc/clinical/#sgbs) has been created and is being
maintained to improve the clinical care and understanding of the
pathogenesis of SGBS. Using an integrated approach employing
epidemiology, molecular genetic characterization of specific GPC3
mutations, and the use of model organisms should rapidly expand
the understanding of this complex disorder.
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SCHOOL OF MEDICINE
