Projects

Developmental Biology of Growth Factor Modulation by Heparan Sulfate

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.


Molecular Genetics of Heparan Sulfate Biosynthesis

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.


Roles of Heparan Sulfate in Human Disease

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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